Review Article Switching Off Key Signaling Survival Molecules ...pneumococcal meningitis [ ]....

Review ArticleSwitching Off Key Signaling Survival Molecules to Switch Onthe Resolution of Inflammation

Denise Alves Perez12 Juliana Priscila Vago23 Rayssa Maciel Athayde12

Alesandra Corte Reis12 Mauro Martins Teixeira2 Lirlacircndia Pires Sousa23

and Vanessa Pinho12

1 Laboratorio de Resolucao da Resposta Inflamatoria Departamento de Morfologia Instituto de Ciencias BiologicasUniversidade Federal de Minas Gerais Avenida Antonio Carlos 6627 Pampulha 31270-901 Belo Horizonte MG Brazil

2 Laboratorio de Imunofarmacologia Departamento de Bioquımica e Imunologia Instituto de Ciencias BiologicasUniversidade Federal de Minas Gerais 31270-901 Belo Horizonte MG Brazil

3 Laboratorio de Sinalizacao inflamacao Departamento de Analises Clınicas e Toxicologicas Faculdade de FarmaciaUniversidade Federal de Minas Gerais 31270-901 Belo Horizonte MG Brazil

Correspondence should be addressed to Vanessa Pinho vpinhoicbufmgbr

Received 14 April 2014 Revised 2 June 2014 Accepted 1 July 2014 Published 17 July 2014

Academic Editor Victor M Baizabal-Aguirre

Copyright copy 2014 Denise Alves Perez et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Inflammation is a physiological response of the immune system to injury or infection but may become chronic In generalinflammation is self-limiting and resolves by activating a termination program named resolution of inflammation It has beenargued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases Resolution of inflammationis an active process that is fine-tuned by the production of proresolving mediators and the shutdown of intracellular signalingmolecules associated with cytokine production and leukocyte survival Apoptosis of leukocytes (especially granulocytes) is a keyelement in the resolution of inflammation and several signaling molecules are thought to be involved in this process Here weexplore key signalingmolecules and somemediators that are crucial regulators of leukocyte survival in vivo and thatmay be targetedfor therapeutic purposes in the context of chronic inflammatory diseases

1 Introduction

Inflammation is a reaction of an organism to cell andtissue damage caused by various types of agents (sterileor not including autoimmune events) Inflammation mayalso be physiological and is thought to be crucial for themaintenance of tissue homeostasis [1ndash5] Important micro-circulatory events occur during the inflammatory processincluding vascular permeability changes in the movementrecruitment and accumulation of leukocytes and the releaseof inflammatory mediators [6] After elimination of theharmful agent the inflammatory process is usually resolvedas seen by the reduction in the number of leukocytes inthe inflammatory site and the reversal of vascular changesResolution is necessary to restore the original architecture

and function of a given tissue Failure to resolve can causepersistent inflammation with consequent maintenance orincrease of tissue destruction [3] It has been argued thatunresolved inflammation or excessive initial inflammationmay be the basis of a variety of chronic inflammatory diseases[7]

The resolution of inflammation is an active process thatis coordinated and controlled by a variety of extracellularand intracellular molecules [4] With the termination of theinflammatory stimulus the reduction of proinflammatorymediators occurs at the site through the decreased syn-thesis and increased catabolism of these molecules [4 8]The release of proresolving mediators also occurs whichprevents further migration and increases apoptotic eventsof leukocytes (primarily granulocytes) [9] In parallel some

Hindawi Publishing CorporationMediators of InflammationVolume 2014 Article ID 829851 11 pageshttpdxdoiorg1011552014829851

2 Mediators of Inflammation

proresolving molecules are able to induce the incoming ofnonphlogistic macrophages to further perpetuate efferocy-tosis of apoptotic granulocytes In doing so proresolvingmolecules reprogrammacrophages to performmore restora-tive and resolutive roles thus amplifying the production ofproresolving molecules and promoting resolution [10 11]These events mark the beginning of the resolution processwhich is essential to reestablish tissue homeostasis [4 8 1012]

Some leucocytes such as granulocytes (mainly neu-trophils and eosinophils) and macrophages are profoundlyinvolved in the inflammatory response Granulocytes releasetoxic compounds and also act as phagocytes together withmacrophages to remove the agent causing inflammationHowever for the inflammatory process to be successful andself-limiting (with the goal of restoring tissue homeostasis)the actions of neutrophils and eosinophils must be finelyregulated [3 4 8] Thus apoptosis of granulocytes followedby the efferocytosis (phagocytosis of apoptotic cells) bymacrophages and an active resolution process are obviousavenues to achieve this goal [6 10 12]

Several signaling molecules including PI3KAkt NF-120581B MAPKs and CDKs have been shown to be involvedin enhancing granulocyte survival in vivo and in vitro [13ndash16] The rationale behind enhanced granulocyte survivalinvolves delaying death of these cells to enable efficienteffector function such as bacterial killing However if notfinely controlled prolonged activation of survival pathwaysand prevention of apoptosis in granulocytes may eventuallydelay inflammation resolution In contrast with themoleculesdescribed above proresolving mediators including AnnexinA1 (AnxA1) hydrogen peroxide (H

2O2) cyclic adenosine

monophosphate (cAMP) TNF-related apoptosis-inducingligand (TRAIL) elevating agents (see Figure 1) and otherspecialized lipid mediators (lipoxin A

4 resolvins maresins

and protectins) perform the opposite action that is theyinduce granulocyte apoptosis Recent studies have shown thatstrategies that modulate apoptosis-controlling proteins maypromote the resolution of the inflammatory process [17ndash22]Therefore potential therapeutic strategies that modulate theresolution pathways may further represent a useful pharma-cological arsenal for the treatment and prevention of variousacute and chronic inflammatory diseases Here we discusssome aspects of the complex signaling network and someinterventions that interfere with key signaling moleculesassociated with leukocyte survival and consequently con-tribute to inflammation resolution and return to homeostasis

2 Signaling Molecules as Crucial Regulators ofthe Resolution of Inflammation

21 Cyclin-Dependent Kinases Cyclin-dependent kinases(CDK) are serinethreonine protein kinases that bind tocyclin to mediate the phosphorylation reactions that areassociated with the progression and regulation of the cellcycle [23] Surprisingly terminally differentiated cells includ-ing neutrophils also express CDKs [24] Previous studieshave demonstrated that human neutrophils express CDK

isoforms and their activity is associated with neutrophillifespan [24ndash28] More recent data have shown that CDKinhibitors (CDKi) drive granulocyte apoptosis and resolveinflammation by downregulating Mcl-1 and upregulatingproapoptotic proteins such as Bim [24 26 27 29ndash31] Inseveral models of inflammation including passively inducedarthritis bleomycin-induced lung injury and carrageenan-elicited acute pleurisy R-roscovitine a selective inhibitor ofcyclin-dependent kinases CDK2 CDK5 CDK7 and CDK9enhanced the resolution of established inflammation Thisresolution was associated with an increase in neutrophilapoptosis in a caspase-dependent manner [24] In murinemodels it has also been reported that the induction ofneutrophil apoptosis with R-roscovitine in conjunction withantibiotic therapy reduces markers of neuronal damage ofpneumococcal meningitis [30] Moreover neutrophil clear-ance mediated through CDK inhibition reduced the lunginflammation induced by lipoteichoic acid Streptococcuspneumonia and bleomycin-induced lung injury models[26 32] R-roscovitine inhibits the CDK7- and CDK9-dependent phosphorylation of RNA polymerase II to blockthe transcriptional capacity of neutrophils which can be akey mechanism associated with neutrophil apoptosis afterCDK inhibition [26] The studies discussed above clearlydemonstrate that CDK inhibitors induce apoptosis and invivo clearance of nonproliferating cells such as granulocytesAT7519 is amore recently investigatedCDK inhibitor that hasbeen evaluated in clinical trials for anticancer therapy [33] Astudy by Alessandri et al demonstrated that AT7519 inducedeosinophil apoptosis and enhanced the resolution of allergicpleurisy [31] AT7519 was also capable of inducing neutrophilapoptosis and accelerating the resolution of inflammationinduced by LPS or Escherichia coli without the impairmentof bacterial clearance [34] Importantly AT7519 has alreadybeen tested to treat patients with refractory solid tumors[33] Altogether these findings suggest that CDK may be auseful therapeutic strategy for the treatment of inflammatorydiseases

22 Mitogen-Activated Protein Kinases (MAPK) andExtracellular-Signal-Regulated Kinase (ERK) The mitogen-activated protein kinases (MAPK) represent a familyof serine threonine kinases that phosphorylate andactivate transcription factors present in the cytoplasmor nucleus to drive the expression of genes and consequentlybiological responses There are three main MAPK-activatedsignaling cascades that lead to differential gene expressionextracellular-signal-regulated kinase ERK12 p38 MAPkinase and c-Jun N-terminal kinases (JNKs) these cascadesare activated by several stimuli to regulate proliferationdifferentiation cell survival mitosis apoptosis and othercell functions [35 36] The MEKERK signaling pathwayhas been targeted in an attempt to promote resolutionof acute inflammation Thus it has been demonstratedthat treatment with U0126 a potent and selective MEK12inhibitor (a kinase upstream ERK12) was able to reduceinflammatory parameters in a murine model of allergicasthma [37] and LPS-induced lung injury [38] Additionally

Mediators of Inflammation 3

Leukocyteaccumulation

Anx

A1

Apoptosis Apoptosis Reprogrammingmacrophage

Apoptosis

cAMPProresolutionmolecules

Modulatingpathways

Process

M2 ou

MREs

M1

Bystr

om et

al

2008

Shel

don

et al

20

13

Efferocytosis

Increased survival ofmacrophage

(Lee et al 2013)

Reviewed byPerretti and DrsquoAcquisto 2009

uarr Baxuarr casp-3

uarr Baxuarr casp-3

darr NF-120581B darr NF-120581B

darr Akt darr Akt

darr Mcl-1

uarr Baxuarr casp-3

darr NF-120581Bdarr Mcl-1

darr ERK

H 2O 2

Lope

s et a

l20

11

Solito

et al

200

3

Dalli e

t al

2013

Vago et

al 2

012

Maderna et al 2005

Dalli et al 2012

Dalli et al 2013

Li et al 2011

Cooray et al 2013

Sousa et al 2009

Sousa et al 2010

Figure 1 Targets to promote granulocyte apoptosis and inflammation resolution During early phase of inflammation production ofproinflammatory mediators and activation of signal survival pathways (PI3KAkt NF-120581B MAPKs and CDKs) promotes leukocyteaccumulation and survival in the inflammatory siteWhile inflammatory response evolves local activationrelease of proresolutionmediatorsoccurs and pathways (H

2O2 AnxA1 and cAMP) that control further granulocyte ingress and turn on a resolution programThese resolution

molecules in addition to proresolving lipid mediators which are not highlighted in this cartoon downregulate survival pathways and activatean apoptosis-associated program in granulocytes Resolutionmolecules are also able to promote efferocytosis and coordinate reprogrammingof macrophages These events will reestablish tissue homeostasis

the use of a specific ERK12 inhibitor (PD98059) augmentedthe resolution of inflammation in a pleurisy modelthis was associated with the inhibition of the production ofneutrophil survival factors at the site of inflammation and theincreased neutrophil apoptosis [39] A recent study in vitrodemonstrated that MSK12 (mitogen- and stress-activatedprotein kinase 1 and 2)mdashtwo kinases phosphorylated byboth ERK12 and p38 MAPKmdashare associated with controlon the induction of cyclooxygenase- (COX-) 2 mRNA andthe IL-10 production through CREB (cAMP responsiveelement-binding protein) in macrophages stimulated or notwith LPS [40] However there is no evidence that MSK12are relevant for resolution of inflammation in vivoThereforealthough the anti-inflammatory effects of MAPK inhibitorshave been clearly defined the potential of these inhibitors topromote inflammation resolution needs to be better clarifiedusing other models of in vivo inflammation

23 Cyclic Adenosine Monophosphate Cyclic adenosinemonophosphate (cAMP) is a ubiquitous second messenger

produced after adenylate cyclase activation that has beenshown to play an important role in modulating the activityof cells involved in the inflammatory process primarilythrough PKA activity [41] Intracellular levels of cAMPare physiologically modulated by agonist ligands (such asPGE2 adenosine and 120573-adrenergic) and are fine-tuned

and controlled by phosphodiesterases (PDEs) which areintracellular enzymes that hydrolyze cAMP [41 42] Inaddition to known anti-inflammatory proprieties of cAMP-elevating agents [41ndash44] emerging data support a role forcAMP in some steps of the resolution process [20 45ndash47]Our research group demonstrated an important role forcAMP in inducing the resolution of acute inflammation bymodulating the apoptosis of granulocytes in vivo [20 45]cAMP elevation which is mimicked by the administrationof cAMP mimetic compounds or promoted by rolipram (aPDE4 inhibitor) induced the resolution of both eosinophilic[45] and neutrophilic inflammation [20] which wasmediated by PKA and dependent on granulocyte apoptosisThe resolution induced by increasing cAMP levels hasbeen associated with the modulation of several molecular


pathways which are important for leukocyte survivalFor example it has been shown that high concentrationsof cAMP decrease prosurvival intracellular moleculesincluding MCL-1 PI3K and NF-120581B and increase levelsof proapoptotic molecules BAX and cleaved caspase-3[20] Lower levels of cAMP may account for the lack ofresolution of inflammation in a murine model of chronicgranulomatous disease [48]

Emerging concepts about the role of cAMP in inflam-mation resolution came first from Bystrom and cols [46]who demonstrated the participation of cAMP in repro-gramming inflammatory macrophages to resolution-phasemacrophages In agreement with these findings a recentpaper showed that cAMP contributes to resolution bypolarizing M1 to M2 macrophages [49] In addition toinducing macrophage reprogramming enhanced levels ofcAMP induced by binding to lysophosphatidylserine (lyso-PS) expressed on apoptotic neutrophils are also involved inefferocytosis [50 51] Lyso-PS acts on the macrophage G2Areceptor and enhances the clearance of these neutrophilsby signaling through the PKA-dependent increase of Rac1activity via an increased production of PGE

2and cAMP

[52] However whether the above-described mechanisms ofcAMP may be applied in in vivo situations of inflammationremains to be determined

cAMP may function as an intermediate of the effects ofcertain proresolutive molecules For example one study sug-gests that RvD1 is able to increase intracellular levels of cAMPand rescue macrophage apoptosis in a cAMP-dependentmanner [47] A recent study by our group demonstratedthat treatment with a PDE4 inhibitor which enhances cAMPinduced resolution of inflammation that was associated withincreased levels of AnxA1 [21] Altogether these data suggestthat cAMP is a crucial control molecule in the resolution ofinflammation Not only is cAMP induced by proresolvingmolecules but it may also induce the release of proresolvingmolecules thus acting at multiple regulatory levels to induceresolution Therefore cAMP-elevating drugs may representa useful therapeutic strategy to induce the resolution ofinflammation

24 Phosphoinositide 3-Kinases Phosphoinositide 3-kinases(PI3Ks) are a family of intracellular lipid kinases that phos-phorylate the 3-OH group of inositol membrane lipidsthus regulating many aspects of cell function including cellmetabolism survival and polarityThis family can be dividedinto three main classes (I II and III) based on structural andbiochemical characteristics [53 54] In mammals isoformsof PI3K are related to signal transduction and each isoformplays a different role [53] Class I is subdivided into twosubclasses IA and IB PI3K120574 is the only member of classIB and is the most highly expressed in cells of the immunesystem This isoform is composed of the p110120574 catalyticsubunit and the p101 regulatory subunit and is activated bythe G120573120574 subunits of G proteins [55 56] PI3Ks are known tobe important in many cell processes related to the immunesystem including cell activation migration [55 57 58] andcell survival via the phosphorylation of Aktprotein kinase B

(PBK) [20 45] PI3Ks are also activated by antigen cytokineand chemokine receptors [59]

Our group has evaluated the role of PI3K120574 in inducingand maintaining the inflammatory process in experimen-tal models In a model of allergic pleurisy in mice theinhibition of PI3K cleared accumulated eosinophils andincreased the number of apoptotic events Experiments usingadoptive transfer of bone marrow cells showed that PI3K120574 onleukocytes was required for the maintenance of eosinophilinflux at the later stages of eosinophilic inflammation [17]These studies suggest that PI3K120574 on leukocytes is relevantfor the maintenance of inflammation and that inhibitorsof these enzymes could potentially impart on resolution ofinflammation

However there are no published studies demonstratingthat selective blockade of PI3K120574 is really proresolutive invivo Blockers of PI3K120574 may have anti-inflammatory effectsin vivo as we have shown in a model of bleomycin-inducedpulmonary inflammation [19] However a definite demon-stration that these enzymes are relevant in vivo is lackingas most published studies have only studied the effects ofpan PI3K inhibitors especially wortmannin and LY294002in preclinical models of inflammation resolution There arenowmany new selective PI3K inhibitors in development [60]Whether such drugs with greater selectivity and safety profilewill resolve inflammation in vivo needs to be studied

25 Nuclear Factor Kappa B Nuclear factor kappa B (NF-120581B)is a transcription factor that regulates immune response toboth injury and infection [61 62] NF-120581B is a convergencepoint of several signal transduction pathways by conveyingthe signals of these molecules to the nucleus and promotingtranscriptional activation of genes associated with inflam-mation and cell survival [62] The activity of NF-120581B isprimarily regulated through interactions with inhibitory I120581BproteinsThephosphorylation of I120581B results in its proteasomedegradation and the release of NF-120581B (usually composed ofp50p65 heterodimers) for nuclear translocation and activa-tion of gene transcription [61 62] Over 750 inhibitors ofthe NF-120581B pathway have been identified including a varietyof natural and synthetic molecules These molecules act byinhibiting NF-120581B nuclear translocationor transactivation orthrough I120581B super repression [63ndash67]

Recently numerous investigations have supported therole of miRNAs in the regulation of NF-120581B miRNAshave been found to be involved in NF-120581B signaling bytargeting NF-120581B regulators and effectors [68 69] Recentstudies have shown that NF-120581B inhibitors may attenuateinflammatory parameters in different experimental modelsof inflammation [70] For example NF-120581B inhibitors possessanti-inflammatory effects in models of lipopolysaccharide-induced lung injury [71] traumatic brain injury [72] col-itis [73] and pulmonary arterial hypertension [74] Fewerstudies have evaluated the effects of NF-120581B inhibitors inthe resolution of inflammation Our research group showedthat inhibition of NF-120581B promotes resolution in establishedmurine models of neutrophilic and eosinophilic inflamma-tion [22 45] The resolution of inflammation induced by


NF-120581B inhibitors in the models of arthritis [22] and allergicpleurisy [45] was associated with enhanced apoptosis ofinflammatory cells

NF-120581B activation usually results in the upregulation ofantiapoptotic genes that may lead to cell survival [64]However NF-120581B may also control genes associated withsurvival and anti-inflammation [70 75] In this sense a fewstudies have shown that NF-120581B inhibitors failed to promotethe resolution of inflammation [20] and actually prolongedthe inflammatory response by preventing leukocyte apoptosis[70 76] Greten and cols also described that NF-120581B couldalso function as a negative posttranslational regulator ofinflammasome activation Therefore it is clear that NF-120581Bmay have dual role both pro- and antiresolution inmodels ofinflammation This duality of function of NF-120581B is likely theresult of the central role of this molecule in the convergenceof several inflammatory signals [70] Whether manipulatingNF-120581B in inflammation will ultimately result in beneficialfunctions clearly deserves further investigation

The discussion above suggests that several signalingpathways have been implicated in leukocyte survival duringinflammatory response It is important to note that eachspecificmolecule associatedwith a signaling pathway cascademay not work in a disconnected manner Crosstalk betweensignaling pathways is likely to be essential for leukocytesurvival and much more work is needed to understand theinteraction between potential resolution inducing pathwaysespecially in the context of the complex in vivo situationof an inflammatory response However as demonstratedabove there are molecules which are crucial for resolutionof inflammation and whose effects may be indeed exploitedtherapeutically [77 78]

3 Molecules Involved in Apoptosisof Granulocytes and Resolution ofthe Inflammatory Response

31 Annexin A1 Annexin A1 (AnxA1) is a 37 kDaglucocorticoid-induced protein firstly identified byits action on phospholipase- (PL-) A2 inhibition andprevention of eicosanoid synthesis [79] AnxA1 is a proteinmember of the annexin superfamily which exerts itsanti-inflammatory activity by binding to receptor ALX(named FPR2 formyl peptide receptor-2 murine) whichis also shared with lipoxins [80] During the initial stepsof acute inflammation AnxA1 limits the recruitmentof leukocytes and the production of proinflammatorymediators [80] During the resolution phase AnxA1 actsby inducing the apoptosis of neutrophils and this effect isassociated with increased expression of cleaved caspase-3and BAX and decreased expression of pERK12 NF-120581Band MCL-1 [21 81ndash83] and increasing efferocytosis bymacrophages [83ndash85] Interestingly activation of FPR2 byAnxA1 and LXA4 skewed M1 macrophages to M2-like cells[86] In this context of macrophage modulation it wasdemonstrated that AnxA1 released from apoptotic cellscontributed to the immunomodulatory effect of these cellson inflammation cells by damping inflammatory monocyte

activation [87] Additionally AnxA1 may induce indirectlythe chemoattraction of monocytes [88] These effectsmdashmigration of monocytes and skewing towards a M2-likephenotypemdashmay be relevant in the context of inflammationbut remain to be determined in vivo

The N-terminal region of AnxA1 is the major effectorportion responsible for the anti-inflammatory action of theprotein [80] However once in the extravascular spacethe major part of the active AnxA1 (37 kDa) containedin neutrophils is cleaved by proteases particularly elastaseand proteinase-3 yielding the inactive AnxA1 (of 33 kDaform) [89 90] As a strategy to deliver anxA1 in vivo weand others have explored the therapeutic potential of anAnxA1 peptidomimetic Ac2-26 which retains the biologicalactivity of the entire protein In a model of acute inflam-mation triggered by LPS the administration of Ac2-26 atthe peak of inflammation resolved inflammation by inducingcaspase-dependent apoptosis of inflammatory cells [21] thismechanism was also demonstrated using a longer peptideAnxA1

2minus50[83] An AnxA1 cleavage-resistant protein and

an AnxA12ndash50 peptide with a mutation on the cleavage site

were demonstrated to be more effective in improving severalparameters of inflammation compared with a full lengthprotein and a peptide that was not mutated at the sites ofproteases action [83 90]

One intriguing characteristic of the FPR receptor is thatit recognizes both proinflammatory and proresolving signalsthus integrating contrasting cues to determine the courseof inflammation [91 92] Cooray and cols revealed thisintriguing receptor characteristic and showed that the anti-inflammatory signal triggered by AnxA1 (Ac2-26 peptide)and LXA4 promotes FPR2 homodimerization and resolutionactivities by inducing p38-induced IL-10 production thisstands in contrast with proinflammatory signals such asSAA that bind to the receptor alone Interestingly Ac2-26 peptide which is a nonselective FPR ligand (binding toboth FPR2 and FPR1) is able to promote the dimerizationof FPR1 and FPR2 and change the proinflammatory natureof FPR1 by transducing JNKcaspase-3 proapoptotic signaland promoting resolution of inflammation [93] These latterfindings would help explain the restorative role of Ac2-26peptide by acting through FPR1 and orchestrating epithelialrepair in a model of mucosal inflammation [94] ThusAnxA1 its peptidomimetics or AnxA1-inducer drugs mayhave great therapeutic potential as resolution inducing drugsin vivo

32 Hydrogen Peroxide The nicotinamide adenine dinu-cleotide phosphate oxidase (NADPH oxidase) expressed inphagocytes is a multisubunit enzyme complex that generateshydrogen peroxide (H

2O2) and other reactive oxygen species

(ROS) [95] Accumulating data has suggested that ROS arenotmerely injurious but can also downregulate inflammationand contribute to the maintenance of tissue homeostasis[96 97] Consistent with this observation various lines ofevidence have indicated a critical role of H

2O2for the natural

resolution of inflammation and regenerationrepair of tissue


by inducing apoptosis in different cell types such as neu-trophil [22] hepatocyte [98] myocytes [97] and endothelial[99] and lymphoma cells [100]

Our group has investigated the effects of H2O2in the

context of the resolution of inflammation Lopes et al demon-strated that H

2O2resolves neutrophilic inflammation by

activating BAX and caspase-3 and the shutting down NF-120581Band PI3K pathways Consistently with the latter observationdeficiency of the gp91phox component of NADPH oxidasewas associated with increased inflammation in a model ofantigen-induced arthritis In vitro H

2O2has been shown to

induce programmed cell death in various cell types includingleukocytes In these cells H

2O2appears to decrease survival

signaling pathways including PI3KAkt the transcriptionfactor NF-120581B and mitochondrial pathways [22 101ndash104]The situation in vivo is much less well known and studieswill be needed to determine the precise molecular pathwaysthat control H

2O2production and the extracellular and

intracellular signaling mechanisms through which H2O2

promotes resolution of inflammation In this sense a recentstudy showing that H

2O2may induce the expression of

AnxA1 raises the hypothesis that AnxA1 could be involvedin the proresolving abilities of this molecule [105] Thereforealthough the proresolving role of H

2O2is of great interest

further studies on its source and mechanisms of action areclearly needed

33 TNF-Related Apoptosis-Inducing Ligand The TNF-related apoptosis-inducing ligand (TRAIL) is a cytokine thatbelongs to the TNF superfamily that was discovered in 1995[106ndash108] TRAIL is able to interact with two proapoptoticdeath receptors TRAIL-R1DR4 and TRAIL-R2DR5 aswell as three decoy receptors without functional deathdomains [109 110] The role of TRAIL in biological systemsis complex Several studies have demonstrated a key roleof TRAIL in controlling a number of different types ofcancer [109ndash115] However some studies have shown thatTRAIL has important functions in the immune systemincluding an immunoregulatory function [116ndash120] TRAILis also involved in the control of some autoimmune diseases[121 122] For example the neutralization of endogenousTRAIL may prevent the resolution of granulomatousexperimental autoimmune thyroiditis [123]

A few studies have demonstrated that TRAIL is able topromote apoptosis of human and murine neutrophils [108124] and may hence promote inflammation resolution Inthis regard it has been shown that the duration of neu-trophilic inflammation is enhanced in TRAIL-deficient mice[108] In addition TRAIL-deficient mice showed an aberrantinflammatory response associated with reduced apoptosisof inflammatory cells and increased collagen depositionin a model of chronic pulmonary inflammation inducedby bleomycin [125] TRAIL was also found to modulateallergic inflammation The treatment with antiTRAIL anti-body blocked apoptosis of T helper type 2 (Th2) cells andeosinophils and enhanced the inflammatory response [126]Although conclusive evidence is lacking for a role of TRAILin the resolution of inflammation [127] the effects of TRAIL

are associated with the apoptosis of leukocytes suggestingTRAILrsquos potential therapeutic use for the treatment of estab-lished inflammatory diseases Agonistic antibodies have beenproduced to treat many cancers the monoclonal antiTRAIL-R1 antibody (mapatumumab) [128] is currently in clinicaldevelopment and five antiTRAIL-R2 antibodies are alsobeing tested (lexatumumab Apomab TRA-8 AMG 655 andLBY135) [129ndash133] Thus these antibodies could potentiallybe explored in the context of inflammation resolution

4 Concluding Remarks

Given the importance of inflammation and its resolutionmany studies have sought to better understand the molec-ular scenario involved in these processes Some of theactors involved in the resolution of inflammation werementioned in the present review and were demonstratedto be potential targets of therapeutic approaches The res-olution of inflammation is a vital process that enablesthe return to homeostasis of the immune system and theorgan affected by inflammation avoiding the development ofchronic and autoimmune diseases [8 134] In vitro studiesprovide essential information about molecular machinerythat helps to elucidate how different intracellular moleculescontrol leukocyte survival in inflammatory sites Howeverthey do not cover the entire complexity of in vivo settingswhich include intracellular pathways and molecules thatare interrelated or codependent [78] Moreover resolutionof inflammation an in vivo phenomenon is much morecomplex than simple apoptosis of leukocytes and includesswitching off proinflammatory pathways efferocytosis andthe function of cells other than leukocytes For examplesome proresolving mediators act in macrophages by rescuingfromapoptosis and by activating them to induce phagocytosisof apoptotic leukocytes (efferocytosis) [53] There is alsoevidence to suggest that nonhematopoietic cells may beinvolved in the context of the resolution of inflammation[135] However studies evaluating the role of epithelial cellsand other nonprofessional phagocytic cells in the resolutionof inflammation are lacking

Future studies should try to integrate current findingswith single signaling molecules with more complex signalingpathways and how they interact with each other all of thesein the complex in vivo situation Consideration should begiven not only to pathways associated with apoptosis ofleukocytes but also to molecules and pathways associatedwith triggering efferocytosis One must also keep in mindthat cells other than leukocytes may respond to resolutioninducing molecules in vivo by releasing secondary mediatorswhich themselves could be more relevant as final mediatorsof resolution New animalmodels in which natural resolutionof inflammation does not occur are clearly needed especiallyin models accompanied by a degree of chronic fibrosis Mostreported studies have been performed in systems in whichresolution eventually occursWhether strategies which speedthe resolution of inflammationwill also resolve inflammationand prevent or reverse fibrosis in a nonresolving chronicmodel needs to be determined Finally one will also need


to take the difficult task of translating experimental findingsinto human diseases Whether proresolving strategies will beaccompanied by significant degree of immunosuppression iscurrently not known and will need to be addressed in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Lirlandia Pires Sousa and Vanessa Pinho contributed equallyto the coordination of this work

Acknowledgments

The authors would like to acknowledge funding from Con-selho Nacional de Desenvolvimento Cientıfico e Tecnologico(CNPq Brazil) Comissao de Aperfeicoamento de Pessoal doEnsino Superior (CAPES Brazil) Fundacao do Amparo aPesquisa de Minas Gerais (FAPEMIG Brazil) The InstitutoNacional de Ciencia e Tecnologia (INCT in Dengue) andthe European Communityrsquos Seventh Framework Programme(FP7-2007-2013 Timer consortium) under Grant agreementHEALTH-F4-2011-281608

References

[1] R Medzhitov ldquoInflammation 2010 new adventures of an oldflamerdquo Cell vol 140 no 6 pp 771ndash776 2010

[2] A A Katzenstein and J L Myers ldquoIdiopathic pulmonaryfibrosis Clinical relevance of pathologic classificationrdquo TheAmerican Journal of Respiratory and Critical Care Medicine vol157 no 4 pp 1301ndash1315 1998

[3] D W Gilroy T Lawrence M Perretti and A G RossildquoInflammatory resolution new opportunities for drug discov-eryrdquo Nature Reviews Drug Discovery vol 3 no 5 pp 401ndash4162004

[4] C N Serhan and J Savill ldquoResolution of inflammation thebeginning programs the endrdquo Nature Immunology vol 6 no12 pp 1191ndash1197 2005

[5] Y Isobe T Kato and M Arita ldquoEmerging roles of eosinophilsand eosinophil-derived lipid mediators in the resolution ofinflammationrdquo Frontiers in Immunology vol 3 Article IDArticle 270 2012

[6] O Chertov D Yang O M Zack Howard and J J OppenheimldquoLeukocyte granule proteins mobilize innate host defenses andadaptive immune responsesrdquo Immunological Reviews vol 177pp 68ndash78 2000

[7] C Nathan and A Ding ldquoNonresolving InflammationrdquoCell vol140 no 6 pp 871ndash882 2010

[8] C N Serhan S D Brain C D Buckley et al ldquoResolution ofinflammation state of the art definitions and termsrdquoTheFASEBJournal vol 21 no 2 pp 325ndash332 2007

[9] C D Buckley D W Gilroy and C N Serhan ldquoProresolvinglipid mediators and mechanisms in the resolution of acuteinflammationrdquo Immunity vol 40 no 3 pp 315ndash327 2014

[10] E L Gautier S Ivanov P Lesnik et al ldquoLocal apoptosis medi-ates clearance of macrophages from resolving inflammation inmicerdquo Blood vol 122 no 15 pp 2714ndash2722 2013

[11] A Sica and AMantovani ldquoMacrophage plasticity and polariza-tion in vivo veritasrdquo Journal of Clinical Investigation vol 122no 3 pp 787ndash795 2012

[12] A Ariel and C N Serhan ldquoNew lives given by cell deathMacrophage differentiation following their encounter withapoptotic leukocytes during the resolution of inflammationrdquoFrontiers in Immunology vol 3 Article ID Article 4 p 4 2012

[13] S M Abraham and A R Clark ldquoDual-specificity phosphatase1 a critical regulator of innate immune responsesrdquo BiochemicalSociety Transactions vol 34 part 6 pp 1018ndash1023 2006

[14] C C Franklin and A S Kraft ldquoConditional expression of themitogen-activated protein kinase (MAPK) phosphatase MKP-1preferentially inhibits p38 MAPK and stress-activated proteinkinase in U937 cellsrdquo Journal of Biological Chemistry vol 272no 27 pp 16917ndash16923 1997

[15] P Chen J Li J Barnes G C Kokkonen J C Leeand Y Liu ldquoRestraint of proinflammatory cytokine biosyn-thesis by mitogen-activated protein kinase phosphatase-1in lipopolysaccharide-stimulated macrophagesrdquo Journal ofImmunology vol 169 no 11 pp 6408ndash6416 2002

[16] K V Salojin I B Owusu K A Millerchip M Potter K APlatt and T Oravecz ldquoEssential role of MAPK phosphatase-1in the negative control of innate immune responsesrdquo Journal ofImmunology vol 176 no 3 pp 1899ndash1907 2006

[17] V Pinho D G Souza MM Barsante et al ldquoPhosphoinositide-3 kinases critically regulate the recruitment and survival ofeosinophils in vivo importance for the resolution of allergicinflammationrdquo Journal of Leukocyte Biology vol 77 no 5 pp800ndash810 2005

[18] V Pinho R D C Russo F A Amaral et al ldquoTissue- andstimulus-dependent role of phosphatidylinositol 3-kinase iso-forms for neutrophil recruitment induced by chemoattractantsin vivordquo Journal of Immunology vol 179 no 11 pp 7891ndash78982007

[19] R C Russo C C Garcia L S Barcelos et al ldquoPhosphoinositide3-kinase 120574 plays a critical role in bleomycin-induced pulmonaryinflammation andfibrosis inmicerdquo Journal of Leukocyte Biologyvol 89 no 2 pp 269ndash282 2011

[20] L P Sousa F Lopes D M Silva et al ldquoPDE4 inhibition drivesresolution of neutrophilic inflammation by inducing apoptosisin a PKA-PI3KAkt-dependent and NF-120581B-independent man-nerrdquo Journal of Leukocyte Biology vol 87 no 5 pp 895ndash9042010

[21] L P Sousa J P Vago C R C Nogueira et al ldquoAnnexin A1modulates natural and glucocorticoid-induced resolution ofinflammation by enhancing neutrophil apoptosisrdquo Journal ofLeukocyte Biology vol 92 no 2 pp 249ndash258 2012

[22] F Lopes F M Coelho V V Costa et al ldquoResolution of neu-trophilic inflammation by H2O2 in antigen-induced arthritisrdquoArthritis and Rheumatism vol 63 no 9 pp 2651ndash2660 2011

[23] M Knockaert P Greengard and L Meijer ldquoPharmacologicalinhibitors of cyclin-dependent kinasesrdquoTrends in Pharmacolog-ical Sciences vol 23 no 9 pp 417ndash425 2002

[24] A G Rossi D A Sawatzky AWalker et al ldquoCyclin-dependentkinase inhibitors enhance the resolution of inflammation bypromoting inflammatory cell apoptosisrdquo Nature Medicine vol12 no 9 pp 1056ndash1064 2006

[25] A E Leitch C Haslett and A G Rossi ldquoCyclin-dependentkinase inhibitor drugs as potential novel anti-inflammatory and


pro-resolution agentsrdquoBritish Journal of Pharmacology vol 158no 4 pp 1004ndash1016 2009

[26] A E Leitch C D Lucas J A Marwick R Duffin C Haslettand A G Rossi ldquoCyclin-dependent kinases 7 and 9 specificallyregulate neutrophil transcription and their inhibition drivesapoptosis to promote resolution of inflammationrdquo Cell Deathand Differentiation vol 19 no 12 pp 1950ndash1961 2012

[27] A E Leitch N A Riley T A Sheldrake et al ldquoThe cyclin-dependent kinase inhibitor R-roscovitine down-regulates Mcl-1 to override pro-inflammatory signalling and drive neutrophilapoptosisrdquo European Journal of Immunology vol 40 no 4 pp1127ndash1138 2010

[28] MRossi SDuan Y Jeong et al ldquoRegulation of theCRL4(Cdt2)ubiquitin ligase and cell-cycle exit by the SCFFbxo11 ubiquitinligaserdquoMolecular Cell vol 49 no 6 pp 1159ndash1166 2013

[29] R Duffin A E Leitch T A Sheldrake et al ldquoThe CDKinhibitor R-roscovitine promotes eosinophil apoptosis bydown-regulation ofMcl-1rdquoTheFEBS Letters vol 583 no 15 pp2540ndash2546 2009

[30] U Koedel T Frankenberg S Kirschnek et al ldquoApoptosis isessential for neutrophil functional shutdown and determinestissue damage in experimental pneumococcalmeningitisrdquoPLoSPathogens vol 5 no 5 Article ID e1000461 2009

[31] A L Alessandri R Duffin A E Leitch et al ldquoInduction ofeosinophil apoptosis by the cyclin-dependent kinase inhibitorAT7519 promotes the resolution of eosinophil-dominant aller-gic inflammationrdquo PLoS ONE vol 6 no 9 Article ID e256832011

[32] A J Hoogendijk J J T H Roelofs J Duitman et al ldquoR-roscovitine reduces lung inflammation induced by Lipoteichoicacid and Streptococcus pneumoniaerdquo Molecular Medicine vol18 no 7 pp 1086ndash1095 2012

[33] D Mahadevan R Plummer M S Squires et al ldquoA phase Ipharmacokinetic and pharmacodynamic study of AT7519 acyclin-dependent kinase inhibitor in patients with refractorysolid tumorsrdquo Annals of Oncology vol 22 no 9 pp 2137ndash21432011

[34] C D Lucas D A Dorward M A Tait et al ldquoDownregu-lation of Mcl-1 has anti-inflammatory pro-resolution effectsand enhances bacterial clearance from the lungrdquo MucosalImmunology vol 7 pp 857ndash868 2014

[35] G Pearson F Robinson T B Gibson et al ldquoMitogen-activatedprotein (MAP) kinase pathways regulation and physiologicalfunctionsrdquo Endocrine Reviews vol 22 no 2 pp 153ndash183 2001

[36] B Kaminska ldquoMAPK signalling pathways as molecular targetsfor anti-inflammatory therapymdashfrom molecular mechanismsto therapeutic benefitsrdquoBiochimica et Biophysica ActamdashProteinsand Proteomics vol 1754 no 1-2 pp 253ndash262 2005

[37] W Duan J H P Chan C H Wong B P Leung and W S FWong ldquoAnti-inflammatory effects of mitogen-activated proteinkinase kinase inhibitor U0126 in an asthma mouse modelrdquoJournal of Immunology vol 172 no 11 pp 7053ndash7059 2004

[38] K Schuh and A Pahl ldquoInhibition of the MAP kinase ERK pro-tects from lipopolysaccharide-induced lung injuryrdquoBiochemicalPharmacology vol 77 no 12 pp 1827ndash1834 2009

[39] D A Sawatzky D A Willoughby P R Colville-Nash andA G Rossi ldquoThe involvement of the apoptosis-modulatingproteins ERK 12 Bcl-x L and Bax in the resolution of acuteinflammation in vivordquo The American Journal of Pathology vol168 no 1 pp 33ndash41 2006

[40] K FMacKenzieMWM van den Bosch S Naqvi et al ldquoMSK1and MSK2 inhibit lipopolysaccharide-induced prostaglandin

production via an interleukin-10 feedback looprdquoMolecular andCellular Biology vol 33 no 7 pp 1456ndash1467 2013

[41] SH Soderling and J A Beavo ldquoRegulation of cAMPand cGMPsignaling new phosphodiesterases and new functionsrdquo CurrentOpinion in Cell Biology vol 12 no 2 pp 174ndash179 2000

[42] C Schudt A Hatzelmann R Beume and H Tenor ldquoPhospho-diesterase inhibitors history of pharmacologyrdquo in Phosphodi-esterases as Drug Targets vol 204 ofHandbook of ExperimentalPharmacology pp 1ndash46 Springer Berlin Germany 2011

[43] M M Teixeira R W Gristwood N Cooper and P GHellewell ldquoPhosphodiesterase (PDE)4 inhibitors anti-inflammatory drugs of the futurerdquo Trends in PharmacologicalSciences vol 18 no 5 pp 164ndash170 1997

[44] D G Souza G D Cassali S Poole andMM Teixeira ldquoEffectsof inhibition of PDE4 and TNF-120572 on local and remote injuriesfollowing ischaemia and reperfusion injuryrdquo British Journal ofPharmacology vol 134 no 5 pp 985ndash994 2001

[45] L P Sousa A F Carmo B M Rezende et al ldquoCyclic AMPenhances resolution of allergic pleurisy by promoting inflam-matory cell apoptosis via inhibition of PI3KAkt and NF-120581BrdquoBiochemical Pharmacology vol 78 no 4 pp 396ndash405 2009

[46] J Bystrom I Evans J Newson et al ldquoResolution-phasemacrophages possess a unique inflammatory phenotype that iscontrolled by cAMPrdquo Blood vol 112 no 10 pp 4117ndash4127 2008

[47] H N Lee and Y J Surh ldquoResolvin D1-mediated NOX2 inac-tivation rescues macrophages undertaking efferocytosis fromoxidative stress-induced apoptosisrdquo Biochemical Pharmacologyvol 86 no 6 pp 759ndash769 2013

[48] R Rajakariar J Newson E K Jackson et al ldquoNonresolvinginflammation in gp91phox-- mice a model of human chronicgranulomatous disease has lower adenosine and cyclic adeno-sine 51015840-monophosphaterdquo Journal of Immunology vol 182 no 5pp 3262ndash3269 2009

[49] K E Sheldon H Shandilya D Kepka-Lenhart M Pol-jakovic A Ghosh and S M Morris Jr ldquoShaping the murinemacrophage phenotype IL-4 and cyclic AMP synergisticallyactivate the arginase I promoterrdquo The Journal of Immunologyvol 191 no 5 pp 2290ndash2298 2013

[50] S C Frasch R F Fernandez-Boyanapalli K Z Berry etal ldquoSignaling via macrophage G2A enhances efferocytosis ofdying neutrophils by augmentation of rac activityrdquo Journal ofBiological Chemistry vol 286 no 14 pp 12108ndash12122 2011

[51] S C Frasch K Z Berry R Fernandez-Boyanapalli etal ldquoNADPH oxidase-dependent generation of lysophos-phatidylserine enhances clearance of activated and dying neu-trophils via G2ArdquoThe Journal of Biological Chemistry vol 283no 48 pp 33736ndash33749 2008

[52] S C Frasch and D L Bratton ldquoEmerging roles for lysophos-phatidylserine in resolution of inflammationrdquo Progress in LipidResearch vol 51 no 3 pp 199ndash207 2012

[53] J A Engelman J Luo and L C Cantley ldquoThe evolutionof phosphatidylinositol 3-kinases as regulators of growth andmetabolismrdquoNature Reviews Genetics vol 7 no 8 pp 606ndash6192006

[54] B Vanhaesebroeck L Stephens and P Hawkins ldquoPI3K sig-nalling the path to discovery and understandingrdquo NatureReviews Molecular Cell Biology vol 13 no 3 pp 195ndash203 2012

[55] J A Deane and D A Fruman ldquoPhosphoinositide 3-kinasediverse roles in immune cell activationrdquo Annual Review ofImmunology vol 22 pp 563ndash598 2004


[56] B Vanhaesebroeck and M D Waterfield ldquoSignaling by dis-tinct classes of phosphoinositide 3-kinasesrdquo Experimental CellResearch vol 253 no 1 pp 239ndash254 1999

[57] T Sasaki J Irie-Sasaki R G Jones et al ldquoFunction of PI3K120574in thymocyte development T cell activation and neutrophilmigrationrdquo Science vol 287 no 5455 pp 1040ndash4046 2000

[58] E Hirsch V L Katanaev C Garlanda et al ldquoCentral role for Gprotein-coupled phosphoinositide 3-kinase 120574 in inflammationrdquoScience vol 287 no 5455 pp 1049ndash1053 2000

[59] D A Fruman and L C Cantley ldquoPhosphoinositide 3-kinase inimmunological systemsrdquo Seminars in Immunology vol 14 no1 pp 7ndash18 2002

[60] T Shao J Wang J G Chen et al ldquoDiscovery of 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides as novel PI3K inhibitors and anticancer agentsby bioisostererdquo European Journal of Medicinal Chemistry vol75 pp 96ndash105 2014

[61] M S Hayden and S Ghosh ldquoNF-120581B the first quarter-centuryremarkable progress and outstanding questionsrdquo Genes ampDevelopment vol 26 no 3 pp 203ndash234 2012

[62] G Bonizzi and M Karin ldquoThe two NF-120581B activation pathwaysand their role in innate and adaptive immunityrdquo Trends inImmunology vol 25 no 6 pp 280ndash288 2004

[63] T D Gilmore and M Herscovitch ldquoInhibitors of NF-120581Bsignaling 785 and countingrdquoOncogene vol 25 no 51 pp 6887ndash6899 2006

[64] B Hoesel and J A Schmid ldquoThe complexity of NF-120581B signalingin inflammation and cancerrdquo Molecular Cancer vol 12 no 1article 86 2013

[65] Q Liu HWu S M Chim et al ldquoSC-514 a selective inhibitor ofIKK120573 attenuates RANKL-induced osteoclastogenesis and NF-120581B activationrdquo Biochemical Pharmacology vol 86 no 12 pp1775ndash1783 2013

[66] R Watanabe R W Azuma J Suzuki et al ldquoInhibition of NF-kappaB activation by a novel IKK inhibitor reduces the severityof experimental autoimmune myocarditis via suppression of T-cell activationrdquoThe American Journal of PhysiologymdashHeart andCirculatory Physiology vol 305 no 12 pp H1761ndashH1771 2013

[67] C S Lee E B Jeong Y J Kim et al ldquoQuercetin-3-O-(210158401015840-galloyl)-120572-l-rhamnopyranoside inhibits TNF-120572-activated NF-120581B-induced inflammatory mediator production by suppressingERK activationrdquo International Immunopharmacology vol 16no 4 pp 481ndash487 2013

[68] X Ma L E Becker Buscaglia J R Barker and Y Li ldquoMicroR-NAs in NF-120581B signalingrdquo Journal of Molecular Cell Biology vol3 no 3 pp 159ndash166 2011

[69] M P Boldin and D Baltimore ldquoMicroRNAs new effectors andregulators of NF-120581Brdquo Immunological Reviews vol 246 no 1 pp205ndash220 2012

[70] T Lawrence D W Gilroy P R Colville-Nash and D AWilloughby ldquoPossible new role for NF-120581B in the resolution ofinflammationrdquo Nature Medicine vol 7 no 12 pp 1291ndash12972001

[71] C F Chian C H Chiang C H Chuang et al ldquoInhibitorof nuclear factor-kappaB SN50 attenuates lipopolysaccharide-induced lung injury in an isolated and perfused rat lungmodelrdquoTranslational Research vol 163 no 3 pp 211ndash220 2014

[72] Y X Sun D K Dai R Liu et al ldquoTherapeutic effect of SN50an inhibitor of nuclear factor-120581B in treatment of TBI in micerdquoNeurological Sciences vol 34 no 3 pp 345ndash355 2013

[73] M El-Salhy K Umezawa O H Gilja J G Hatlebakk DGundersen and T Hausken ldquoAmelioration of severe TNBSinduced colitis by novel AP-1 and NF-120581B inhibitors in ratsrdquoTheScientific World Journal vol 2014 Article ID 813804 8 pages2014

[74] SHosokawa GHaraguchi A Sasaki et al ldquoPathophysiologicalroles of nuclear factor kappaB (NF-kB) in pulmonary arterialhypertension effects of synthetic selective NF-kB inhibitorIMD-0354rdquo Cardiovascular Research vol 99 no 1 pp 35ndash432013

[75] T Lawrence and C Fong ldquoThe resolution of inflammationanti-inflammatory roles for NF-120581Brdquo International Journal ofBiochemistry and Cell Biology vol 42 no 4 pp 519ndash523 2010

[76] F R Greten M C Arkan J Bollrath et al ldquoNF-120581B is anegative regulator of IL-1120573 secretion as revealed by genetic andpharmacological inhibition of IKK120573rdquo Cell vol 130 no 5 pp918ndash931 2007

[77] L P Sousa A L Alessandri V Pinho et al ldquoPharmacologicalstrategies to resolve acute inflammationrdquo Current Opinion inPharmacology vol 13 no 4 pp 625ndash631 2013

[78] A L Alessandri L P Sousa C D Lucas A G Rossi V Pinhoand M M Teixeira ldquoResolution of inflammation mechanismsand opportunity for drug developmentrdquo Pharmacology andTherapeutics vol 139 no 2 pp 189ndash212 2013

[79] R J Flower and G J Blackwell ldquoAnti-inflammatory steroidsinduce biosynthesis of a phospholipase A

2inhibitor which

prevents prostaglandin generationrdquo Nature vol 278 no 5703pp 456ndash459 1979

[80] M Perretti and F DrsquoAcquisto ldquoAnnexin A1 and glucocorticoidsas effectors of the resolution of inflammationrdquo Nature ReviewsImmunology vol 9 no 1 pp 62ndash70 2009

[81] L Parente and E Solito ldquoAnnexin 1 more than an anti-phospholipase proteinrdquo Inflammation Research vol 53 no 4pp 125ndash132 2004

[82] E Solito A Kamal F Russo-Marie J C Buckingham SMarullo andM Perretti ldquoA novel calcium-dependent proapop-totic effect of annexin 1 on human neutrophilsrdquo The FASEBJournal vol 17 no 11 pp 1544ndash1546 2003

[83] J Dalli A P Consalvo V Ray et al ldquoProresolving andtissue-protective actions of annexin A1-based cleavage-resistantpeptides are mediated by formyl peptide receptor 2lipoxin A4receptorrdquo Journal of Immunology vol 190 no 12 pp 6478ndash64872013

[84] P Maderna S Yona M Perretti and C Godson ldquoMod-ulation of phagocytosis of apoptotic neutrophils by super-natant fromdexamethasone-treatedmacrophages and annexin-derived peptide Ac2-26rdquo Journal of Immunology vol 174 no 6pp 3727ndash3733 2005

[85] J Dalli C P Jones D M Cavalcanti S H Farsky M Perrettiand S M Rankin ldquoAnnexin A1 regulates neutrophil clearanceby macrophages in the mouse bone marrowrdquo The FASEBJournal vol 26 no 1 pp 387ndash396 2012

[86] Y Li L Cai H Wang et al ldquoPleiotropic regulation ofmacrophage polarization and tumorigenesis by formyl peptidereceptor-2rdquo Oncogene vol 30 no 36 pp 3887ndash3899 2011

[87] D Pupjalis J Goetsch D J Kottas V Gerke and URescher ldquoAnnexin A1 released from apoptotic cells acts throughformyl peptide receptors to dampen inflammatory monocyteactivation via JAKSTATSOCS signallingrdquo EMBO MolecularMedicine vol 3 no 2 pp 102ndash114 2011

[88] K E Blume S Soeroes H Keppeler et al ldquoCleavage ofannexin A1 by ADAM10 during secondary necrosis generates


a monocytic ldquofind-merdquo signalrdquo Journal of Immunology vol 188no 1 pp 135ndash145 2012

[89] S M Oliani and M Perretti ldquoCell localization of the anti-inflammatory protein annexin 1 during experimental inflam-matory responserdquo Italian Journal of Anatomy and Embryologyvol 106 no 2 supplement 1 pp 69ndash77 2001

[90] M Pederzoli-Ribeil F Maione D Cooper et al ldquoDesign andcharacterization of a cleavage-resistant Annexin A1 mutant tocontrol inflammation in the microvasculaturerdquo Blood vol 116no 20 pp 4288ndash4296 2010

[91] J G Filep ldquoResolution of inflammation leukocytes and molec-ular pathways as potential therapeutic targetsrdquo Frontiers inImmunology vol 4 p 256 2013

[92] J G Filep ldquoGlucocorticoid protection against myocardialischemia-reperfusion injury central role for the PGD2-Nrf2pathwayrdquo Hypertension vol 63 no 1 pp 22ndash23 2014

[93] S N Cooray T Gobbetti T Montero-Melendez et al ldquoLigand-specific conformational change of theG-protein-coupled recep-tor ALXFPR2 determines proresolving functional responsesrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 110 no 45 pp 18232ndash18237 2013

[94] G Leoni A Alam P Alexander Neumann et al ldquoAnnexinA1 formyl peptide receptor and NOX1 orchestrate epithelialrepairrdquo The Journal of Clinical Investigation vol 123 no 1 pp443ndash454 2013

[95] G J Gardiner S N Deffit S McLetchie et al ldquoA role forNADPHoxidase in antigen presentationrdquoFrontiers in Immunol-ogy vol 4 article 295 2013

[96] A van der Vliet and Y M Janssen-Heininger ldquoHydrogenperoxide as a damage signal in tissue injury and inflamma-tion murderer mediator or messengerrdquo Journal of CellularBiochemistry vol 115 no 3 pp 427ndash435 2014

[97] K Wang L Jiang G Deng et al ldquoHeat shock protein 70 inter-acts with nucleolin and inhibits its cleavage down-regulationand apoptosis induced by hydrogen peroxide in myocytesrdquoTheJournal of Biological Chemistry 2010

[98] S Kim H Jung D Hyun E Park Y Kim and C LimldquoGlutathione reductase plays an anti-apoptotic role againstoxidative stress in human hepatoma cellsrdquo Biochimie vol 92no 8 pp 927ndash932 2010

[99] W Fang H Li and L Zhou ldquoProtective effects of prostaglandine 1 on human umbilical vein endothelial cell injury induced byhydrogen peroxiderdquo Acta Pharmacologica Sinica vol 31 no 4pp 485ndash492 2010

[100] F Klamt S Zdanov R L Levine et al ldquoOxidant-inducedapoptosis is mediated by oxidation of the actin-regulatoryprotein cofilinrdquoNature Cell Biology vol 11 no 10 pp 1241ndash12462009

[101] J Li N P Gall D J Grieve M Chen and A M ShahldquoActivation of NADPH oxidase during progression of cardiachypertrophy to failurerdquo Hypertension vol 40 no 4 pp 477ndash484 2002

[102] C ChenM ChowWHuang Y Lin andY Chang ldquoFlavonoidsinhibit tumor necrosis factor-120572-induced up-regulation of inter-cellular adhesion molecule-1 (ICAM-1) in respiratory epithe-lial cells through activator protein-1 and nuclear factor120581BStructure-activity relationshipsrdquo Molecular Pharmacology vol66 no 3 pp 683ndash693 2004

[103] M C Carreras and J J Poderoso ldquoMitochondrial nitric oxide inthe signaling of cell integrated responsesrdquoTheAmerican Journalof PhysiologymdashCell Physiology vol 292 no 5 pp C1569ndashC15802007

[104] G Groeger C Quiney and T G Cotter ldquoHydrogen peroxideas a cell-survival signaling moleculerdquo Antioxidants and RedoxSignaling vol 11 no 11 pp 2655ndash2671 2009

[105] C J Yu C J Ko C H Hsieh et al ldquoProteomic analysisof osteoarthritic chondrocyte reveals the hyaluronic acid-regulated proteins involved in chondroprotective effect underoxidative stressrdquo Journal of Proteomics vol 99 pp 40ndash53 2014

[106] S R Wiley K Schooley P J Smolak et al ldquoIdentificationand characterization of a new member of the TNF family thatinduces apoptosisrdquo Immunity vol 3 no 6 pp 673ndash682 1995

[107] R M Pitti S A Marsters S Ruppert C J Donahue A Mooreand A Ashkenazi ldquoInduction of apoptosis by Apo-2 ligand anew member of the tumor necrosis factor cytokine familyrdquoTheJournal of Biological Chemistry vol 271 no 22 pp 12687ndash126901996

[108] E E McGrath H M Marriott A Lawrie et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) regulates inflammatoryneutrophil apoptosis and enhances resolution of inflammationrdquoJournal of Leukocyte Biology vol 90 no 5 pp 855ndash865 2011

[109] B Pennarun J H Kleibeuker T Oenema J H Stegehuis EG E de Vries and S de Jong ldquoInhibition of IGF-1R-dependentPI3K activation sensitizes colon cancer cells specifically toDR5-mediated apoptosis but not to rhTRAILrdquo Analytical CellularPathology vol 33 no 5-6 pp 229ndash244 2010

[110] B Pennarun A Meijer E G E de Vries J H Kleibeuker FKruyt and S de Jong ldquoPlaying the DISC turning on TRAILdeath receptor-mediated apoptosis in cancerrdquo Biochimica etBiophysica Acta vol 1805 no 2 pp 123ndash140 2010

[111] K Zhou Y Yan and S Zhao ldquoEsophageal cancer-selectiveexpression of TRAIL mediated by MREs of miR-143 and miR-122rdquo Tumor Biology vol 35 no 6 pp 5787ndash5795 2014

[112] Y Liu Z Yang C Gong et al ldquoQuercetin enhances apoptoticeffect of TRAIL in ovarian cancer cells through ROS mediatedCHOP-death receptor 5 pathwayrdquo Cancer Science vol 105 no5 pp 520ndash527 2014

[113] W C Lin H F Tsai H J Liao et al ldquoHelicobacter pylorisensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells throughregulation of FLIPrdquo Cell Death and Disease vol 5 Article IDe1109 2014

[114] P M Holland ldquoDeath receptor agonist therapies for cancerwhich is the right TRAILrdquo Cytokine amp Growth Factor Reviewsvol 25 no 2 pp 185ndash193 2014

[115] C Jennewein S Karl B Baumann OMicheau K-M Debatinand S Fulda ldquoIdentification of a novel pro-apoptotic role of NF-120581B in the regulation of TRAIL- and CD95-mediated apoptosisof glioblastoma cellsrdquo Oncogene vol 31 no 11 pp 1468ndash14742012

[116] A Collison P S Foster and JMattes ldquoEmerging role of tumournecrosis factor-related apoptosis-inducing ligand (TRAIL) as akey regulator of inflammatory responsesrdquo Clinical and Experi-mental Pharmacology and Physiology vol 36 no 11 pp 1049ndash1053 2009

[117] O Aktas U Schulze-Topphoff and F Zipp ldquoThe role ofTRAILTRAIL receptors in central nervous system pathologyrdquoFrontiers in Bioscience vol 12 no 8 pp 2912ndash2921 2007

[118] K Steinwede S Henken J Bohling et al ldquoTNF-relatedapoptosis-inducing ligand (TRAIL) exerts therapeutic efficacyfor the treatment of pneumococcal pneumonia inmicerdquo Journalof Experimental Medicine vol 209 no 11 pp 1937ndash1952 2012


[119] S J Zheng J Jiang H Shen and Y H Chen ldquoReducedapoptosis and ameliorated listeriosis in TRAIL-null micerdquoJournal of Immunology vol 173 no 9 pp 5652ndash5658 2004

[120] C A Benedict and C F Ware ldquoTrail not just for tumorsanymorerdquo The Journal of Experimental Medicine vol 209 no11 pp 1903ndash1906 2012

[121] A Anel and L Martinez-Lostao ldquoApo2ltrail New insightsin the treatment of autoimmune disordersrdquo Recent Patents onInflammation and Allergy Drug Discovery vol 5 no 3 pp 184ndash199 2011

[122] E Salehi M Vodjgani A Massoud et al ldquoIncreased expressionof TRAIL and its receptors on peripheral T-cells in type 1diabetic patientsrdquo Iranian Journal of Immunology vol 4 no 4pp 197ndash205 2007

[123] Y Fang G C Sharp H Yagita andH Braley-Mullen ldquoA criticalrole for TRAIL in resolution of granulomatous experimentalautoimmune thyroiditisrdquo Journal of Pathology vol 216 no 4pp 505ndash513 2008

[124] S A Renshaw J S Parmar V Singleton et al ldquoAccelerationof human neutrophil apoptosis by TRAILrdquo The Journal ofImmunology vol 170 no 2 pp 1027ndash1033 2003

[125] E E McGrath A Lawrie H M Marriott et al ldquoDeficiencyof tumour necrosis factor-related apoptosis-inducing ligandexacerbates lung injury and fibrosisrdquo Thorax vol 67 no 9 pp796ndash803 2012

[126] L Faustino D M Fonseca E B Florsheim et al ldquoTumornecrosis factor-related apoptosis-inducing ligand mediates theresolution of allergic airway inflammation induced by chronicallergen inhalationrdquoMucosal Immunology 2014

[127] A E Leitch C D Lucas and A G Rossi ldquoEditorial neutrophilapoptosis hot on the TRAIL of inflammatory resolutionrdquoJournal of Leukocyte Biology vol 90 no 5 pp 841ndash843 2011

[128] J von Pawel J H Harvey D R Spigel et al ldquoPhase IItrial of mapatumumab a fully human agonist monoclonalantibody to tumor necrosis factor-related apoptosis-inducingligand receptor 1 (TRAIL-R1) in combination with paclitaxeland carboplatin in patients with advanced non-small-cell lungcancerrdquo Clinical Lung Cancer vol 15 no 3 pp 188e2ndash196e22013

[129] B Engesaeligter O Engebraaten V A Floslashrenes and G MMaeliglandsmo ldquoDacarbazine and the agonistic TRAIL receptor-2antibody lexatumumab induce synergistic anticancer effects inmelanomardquo PLoS ONE vol 7 no 9 Article ID e45492 2012

[130] H Jin R Yang J Ross et al ldquoCooperation of the agonistic DR5antibody apomabwith chemotherapy to inhibit orthotopic lungtumor growth and improve survivalrdquo Clinical Cancer Researchvol 14 no 23 pp 7733ndash7740 2008

[131] H M Amm T Zhou A D Steg H Kuo Y Li and D JBuchsbaum ldquoMechanisms of drug sensitization to TRA-8 anagonistic death receptor 5 antibody involve modulation ofthe intrinsic apoptotic pathway in human breast cancer cellsrdquoMolecular Cancer Research vol 9 no 4 pp 403ndash417 2011

[132] C S Fuchs M Fakih L Schwartzberg et al ldquoTRAIL receptoragonist conatumumab with modified FOLFOX6 plus beva-cizumab for first-line treatment of metastatic colorectal cancera randomized phase 1b2 trialrdquoCancer vol 119 no 24 pp 4290ndash4298 2013

[133] A Natoni M MacFarlane S Inoue et al ldquoTRAIL signalsto apoptosis in chronic lymphocytic leukaemia cells primarilythrough TRAIL-R1 whereas cross-linked agonistic TRAIL-R2antibodies facilitate signalling via TRAIL-R2rdquo British Journal ofHaematology vol 139 no 4 pp 568ndash577 2007

[134] A Ortega-GomezM Perretti andO Soehnlein ldquoResolution ofinflammation an integrated viewrdquo EMBO Molecular Medicinevol 5 no 5 pp 661ndash674 2013

[135] A Gall P Treuting K B Elkon et al ldquoAutoimmunity initiatesin nonhematopoietic cells and progresses via lymphocytes in aninterferon-dependent autoimmune diseaserdquo Immunity vol 36no 1 pp 120ndash131 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


proresolving molecules are able to induce the incoming ofnonphlogistic macrophages to further perpetuate efferocy-tosis of apoptotic granulocytes In doing so proresolvingmolecules reprogrammacrophages to performmore restora-tive and resolutive roles thus amplifying the production ofproresolving molecules and promoting resolution [10 11]These events mark the beginning of the resolution processwhich is essential to reestablish tissue homeostasis [4 8 1012]

Some leucocytes such as granulocytes (mainly neu-trophils and eosinophils) and macrophages are profoundlyinvolved in the inflammatory response Granulocytes releasetoxic compounds and also act as phagocytes together withmacrophages to remove the agent causing inflammationHowever for the inflammatory process to be successful andself-limiting (with the goal of restoring tissue homeostasis)the actions of neutrophils and eosinophils must be finelyregulated [3 4 8] Thus apoptosis of granulocytes followedby the efferocytosis (phagocytosis of apoptotic cells) bymacrophages and an active resolution process are obviousavenues to achieve this goal [6 10 12]

Several signaling molecules including PI3KAkt NF-120581B MAPKs and CDKs have been shown to be involvedin enhancing granulocyte survival in vivo and in vitro [13ndash16] The rationale behind enhanced granulocyte survivalinvolves delaying death of these cells to enable efficienteffector function such as bacterial killing However if notfinely controlled prolonged activation of survival pathwaysand prevention of apoptosis in granulocytes may eventuallydelay inflammation resolution In contrast with themoleculesdescribed above proresolving mediators including AnnexinA1 (AnxA1) hydrogen peroxide (H

2O2) cyclic adenosine

monophosphate (cAMP) TNF-related apoptosis-inducingligand (TRAIL) elevating agents (see Figure 1) and otherspecialized lipid mediators (lipoxin A

4 resolvins maresins

and protectins) perform the opposite action that is theyinduce granulocyte apoptosis Recent studies have shown thatstrategies that modulate apoptosis-controlling proteins maypromote the resolution of the inflammatory process [17ndash22]Therefore potential therapeutic strategies that modulate theresolution pathways may further represent a useful pharma-cological arsenal for the treatment and prevention of variousacute and chronic inflammatory diseases Here we discusssome aspects of the complex signaling network and someinterventions that interfere with key signaling moleculesassociated with leukocyte survival and consequently con-tribute to inflammation resolution and return to homeostasis

2 Signaling Molecules as Crucial Regulators ofthe Resolution of Inflammation

21 Cyclin-Dependent Kinases Cyclin-dependent kinases(CDK) are serinethreonine protein kinases that bind tocyclin to mediate the phosphorylation reactions that areassociated with the progression and regulation of the cellcycle [23] Surprisingly terminally differentiated cells includ-ing neutrophils also express CDKs [24] Previous studieshave demonstrated that human neutrophils express CDK

isoforms and their activity is associated with neutrophillifespan [24ndash28] More recent data have shown that CDKinhibitors (CDKi) drive granulocyte apoptosis and resolveinflammation by downregulating Mcl-1 and upregulatingproapoptotic proteins such as Bim [24 26 27 29ndash31] Inseveral models of inflammation including passively inducedarthritis bleomycin-induced lung injury and carrageenan-elicited acute pleurisy R-roscovitine a selective inhibitor ofcyclin-dependent kinases CDK2 CDK5 CDK7 and CDK9enhanced the resolution of established inflammation Thisresolution was associated with an increase in neutrophilapoptosis in a caspase-dependent manner [24] In murinemodels it has also been reported that the induction ofneutrophil apoptosis with R-roscovitine in conjunction withantibiotic therapy reduces markers of neuronal damage ofpneumococcal meningitis [30] Moreover neutrophil clear-ance mediated through CDK inhibition reduced the lunginflammation induced by lipoteichoic acid Streptococcuspneumonia and bleomycin-induced lung injury models[26 32] R-roscovitine inhibits the CDK7- and CDK9-dependent phosphorylation of RNA polymerase II to blockthe transcriptional capacity of neutrophils which can be akey mechanism associated with neutrophil apoptosis afterCDK inhibition [26] The studies discussed above clearlydemonstrate that CDK inhibitors induce apoptosis and invivo clearance of nonproliferating cells such as granulocytesAT7519 is amore recently investigatedCDK inhibitor that hasbeen evaluated in clinical trials for anticancer therapy [33] Astudy by Alessandri et al demonstrated that AT7519 inducedeosinophil apoptosis and enhanced the resolution of allergicpleurisy [31] AT7519 was also capable of inducing neutrophilapoptosis and accelerating the resolution of inflammationinduced by LPS or Escherichia coli without the impairmentof bacterial clearance [34] Importantly AT7519 has alreadybeen tested to treat patients with refractory solid tumors[33] Altogether these findings suggest that CDK may be auseful therapeutic strategy for the treatment of inflammatorydiseases

22 Mitogen-Activated Protein Kinases (MAPK) andExtracellular-Signal-Regulated Kinase (ERK) The mitogen-activated protein kinases (MAPK) represent a familyof serine threonine kinases that phosphorylate andactivate transcription factors present in the cytoplasmor nucleus to drive the expression of genes and consequentlybiological responses There are three main MAPK-activatedsignaling cascades that lead to differential gene expressionextracellular-signal-regulated kinase ERK12 p38 MAPkinase and c-Jun N-terminal kinases (JNKs) these cascadesare activated by several stimuli to regulate proliferationdifferentiation cell survival mitosis apoptosis and othercell functions [35 36] The MEKERK signaling pathwayhas been targeted in an attempt to promote resolutionof acute inflammation Thus it has been demonstratedthat treatment with U0126 a potent and selective MEK12inhibitor (a kinase upstream ERK12) was able to reduceinflammatory parameters in a murine model of allergicasthma [37] and LPS-induced lung injury [38] Additionally



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Acknowledgments


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Acknowledgments


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Review Article Switching Off Key Signaling Survival Molecules ...pneumococcal meningitis [ ]....

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