Omega 3 and its impact on immune...

Omega‐3 and its impact on immune health:

exploring the potential of omega‐3

November 20th, 2014

Food Matters Live, London

Session: Capitalising on the immunity 'super' trend

Omega‐3 and its impact on immune health

Gerard Bannenberg


Objectives

Omega‐3: A central role in the inflammatory response

Understanding the actions of long chain omega‐3 poly‐unsaturated fatty acids (LC omega‐3 PUFA) in the immune system: formation and actions omega‐3‐derived lipid mediators

Evolution in the field and why food matters


“Omega‐3” ‐ a structural descriptor of a functional group

LC omega‐3 PUFA:

EPA eicosapentaenoic acid (C20:5)

DHA docosahexaenoic acid (C22:6)

EPA and DHA can be considered “conditionally” in/dispensableessential fatty acids

Discovery of essential fatty acids.A. Spector and H. Kim. J. Lipid Research Nov. 10, 2014.


Is there a role for EPA and DHA in the immune system and do LC‐omega‐3

PUFA support immune health?

Historical perspectives on the impact of n‐3 and n‐6 nutrients on health.Bill Lands. Progress in Lipid Research 55, 2014.


Enders et al. New Engl. J. Med. 320, 1989

Exud

ate

prot

ein

(mg)

(ext

race

llula

r)

0 42 12 24 48 72Time (h)

2

4

6

8* *

**‡

*‡

*‡

Cel

l num

ber (

x106

)

5

10

15

20

25

0

Total exudate cellsPMNMononuclear cells

The inflammatory response : time course ‐ leukocytes and exudate protein

Pro‐inflammatory phase

Resolution phaseZymosan A‐stimulated peritonitis in mouse(1 mg i.p.)

Bannenberg et al. J. Immunol. 2005Molecular circuits of resolution: formation and actions of resolvins and protectins.

Lawrence, Willoughby, Gilroy, Nat. Rev. Immunol. 2002Anti‐inflammatory lipid mediators and insights into the resolution of inflammation.

Time

Neutrophil infiltration

Inflammation(pro‐inflammatory

phase)

Resolution(removal of neutrophilic

exudate)

Neutrophil

Microbial infection

Endothelial cell

Monocyte

Macrophage

Neutrophil adhesion to endothelium,adhesion, chemotaxis, diapedesis &activation

Neutrophil phagocytosisof microbes

Neutrophils die by apoptosis

Monocyte migration and differentiation to macrophages

Non‐phlogistic phagocytosisof apoptotic neutrophils

Macrophage egress to lymph nodes or undergo apoptosis

Cel

l num

ber

(x10

6 )

5

10

15

0 4 24 48 72 Time (h)

100%

50%

(Duration)R50 = 7.5x106

T50 = 20 h

12

I PMN=mono = 24 h

PMN

Mononuclear cells

Ri8 h

(Magnitude)max = 15 x 106

Tmax = 12 h

The resolution of acute inflammation; A definition in operative and quantitative terms

by the following Resolution Indices

Molecular circuits of resolution: formation and actions of resolvins and protectins. G. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, KH. Gotlinger, S. Hong & CN Serhan. J. Immunol. 2005.


0

50

100

150

ng/m

ouse

0

IL-6 ++

12 24 48 722 4

Time (h)

ng/m

ouse

0

5

10

15

MIP-2 ++

JE (MCP-1)*KC (IL-8) ++

0

0.3

0.6

0.9

1.2

1.5TGF-

ng/m

ouse SDF-1 *

MIP-1 ++

TNF- ++

ng/m

ouse

0

0.5

1.0

1.5

2.0

RANTES*

GM-CSF ++

IFN- *

IL-13*

IL-10 ++

IL-4 ++

ng/m

ouse

IL-12 ++

0.025

0.050

0.075

0

Temporal profiles of cytokines and chemokines

resolution

Temporal profiles of DHA‐derived lipid mediators

DHA

17S-H(p)DHA

10,17S-docosatriene

Time (h)0

1

2

3

4 12 24 48 72

Am

ount

(ng)

per

mou

se

2

*

###

resolution

G. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, KH. Gotlinger, S. Hong & CN Serhan.Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 2005.


Hong et al, JBC 278, 2003; Serhan, J.Immunol. 176, 2006; Yamada FASEBJ 2011

Specialized Pro‐resolving lipid Mediators ‐ SPMs

Arachidonic acid EPA DHA

Prostanoids:PGE2PGI2PGF2αPGD2

Thromboxane A212‐HHT

Leukotrienes:Leukotriene B4Cysteinyl‐leukotrienes

Lipoxins:Lipoxins (LXA4 / LXB4)

“3‐series” Prostanoids:PGE3PGI3PGF3αPGD3

TXB3Leukotriene B5

E‐series resolvins:RvE1RvE2RvE3

12‐OH‐17,18‐EpETE

D‐series resolvins:RvD1RvD2RvD3RvD4RvD5RvD6

Protectin D1 (PD1 / NPD1)10S,17S‐dihydroxylated DHA

Maresins (MaR1, MaR2)14‐Hydroxy‐sulfido‐conjugates14,20‐diHDHA

Specific SPMs are formed at defined time intervals during resolution

J Dalli, J Winkler, R Colas, H Arnardottir, C Cheng, N. Chiang, N Petasis & CN Serhan.Resolvin D3 and aspirin‐triggered resolvin D3 are potent immunoresolvents.Chem. Biol. 2013.

resolution

Lipoxin A4 Lipoxin B4

COOH

OH

OHHO OH

COOH

OHHO

Epithelia or monocytes

15-lipoxygenase 5-lipoxygenasePMN

15S-H(p)ETE Leukotriene A4

5-lipoxygenase 12-lipoxygenasePlatelets

COOH

O(O)H

PMN

OCOOH

NSAIDs

Eicosanoids:ProstaglandinsLeukotrienesThromboxane

Arachidonic acidCOOH

Cyclooxygenase

Lipoxin biosynthesis

Formation of Resolvin E1

Eicosapentaenoic acid(EPA; C20:5)

18R-HEPE

5S-hydroperoxy-18R-hydroxy-EPE

5S,12S,18R-EPE(Resolvin E1; RvE1)

acetylated-COX2 /cytochrome P450

(unknown endogenous/microbial)

5-lipoxygenase(PMN)

COOH

COOH

O(O)H

COOH

O(O)H

O(O)HCOOH

OH

OH

OH

Epoxide formationand rearrangement with incorporation

of water

Serhan, J. Exp. Med. 192, 2000

Aspirin+

+ Lipoxin A4 stableanalogue (ATLa)

0

4

8

12

16

0 4 8 12 16 20 24 28

max = 13.2x106

Tmax ~ 12 hr

Ri~12 hr

T50 ~ 24 hr

cell

num

ber (

x106

)

Time (h)

Acute Inflammation

0

4

8

12

16

0 4 8 12 16 20 24 28

Ri~13 hr

T50 ~ 24 hrR50 = 8.25x106

cell

num

ber (

x106

)

Time (h)

max = 16.5x106

Tmax ~ 11 hr+ RVE1

0

4

8

12

16

0 4 8 12 16 20 24 28

Ri~12 hr

T50 ~ 20 hr

max = 12x106

Tmax ~ 8 hr

cell

num

ber (

x106

)

Time (h)

+ protectin D1

0

4

8

12

16

0 4 8 12 16 20 24 28

Ri~6 hr

T50 ~ 11 hr

cell

num

ber (

x106

)Time (h)

max = 10x106

Tmax ~ 5 hr

Modulation of inflammation and resolutionOmega‐3 and its impact on immune health

G. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, KH. Gotlinger, S. Hong & CN Serhan.Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 2005.


Important indications

1. Resolution of inflammation is not a passive process

2. Resolution can be activated

3. Anti‐inflammation is not the same as pro‐resolution

LC omega‐3‐derived lipid mediators play an important role in endogenousanti‐inflammation and the resolution of inflammation

SPMs are lipid mediators which actively regulate a concerted set of cellular actions that promote the resolution of inflammation

Inhibit• Chemotaxis• Diapedesis• Transmigration• Degranulation

Stimulate• Adherence• Chemotaxis• Non-phlogisticphagocytosis

Stimulate• Non-phlogisticphagocytosis ofapoptotic PMN PMN

Monocyte

Macrophage

SPMsInhibit• IL-12 production • Migration

Dendritic cells

Regulate• IL-8 & BPI

gene expression• NF-κB mediated

transcription

Inhibit• TNF secretion

Inhibit• Chemotaxis• Allergen-induced

trafficking

T-cells

Eosinophils

Epithelial cells

Omega-3 and its impact on immune health

LC omega‐3 and omega‐6 derived anti‐inflammatory lipid mediators function as endogenous receptor ligands

Cash et al, Drug Discovery Today 2014

Cel

l num

ber (

x106

)

5

10

15

20

25

0

Time (h)

PMN

The inflammatory response and “Immune Health”

0 42 12 24 48 72

Anti‐inflammatory

Action

Pro‐resolutionAnti‐inflammatory + resolution toxicResolution toxicAnti‐inflammatory + pro‐resolution

Redefining the importance of food and dietary components as anti-inflammatory and/or pro-resolving for immune health

- Which foods, nutrients, and diets are pro-resolving and drive resolution of inflammation?

- Which compounds or conditions interfere with resolution?

- Can we ascribe chronic inflammatory disease to defects in resolution?


SPMs stimulate phagocytosis

No FITC‐zymosan FITC‐zymosan

RvE1(10 nM)

without

RvE1

T. Ohira, M Arita, K Omori, A Recchiuti, T. van Dyke & CN Serhan.Resolvin E1 receptor activation signals phosphorylation and phagocytosis. JBC 2009.


J Dalli et al. Chem. Biol. 2013.

SPMs stimulate clearance of infections

N. Chiang, G Fredman, F Bäckhed, S h, T Vickery, B Schmidt & CN Serhan.Infection regulates pro‐resolving mediators that lower antibiotic requirements. Nature 2010.

E. coli aloneE. coli + RvD1E. coli + ciprofloxacinE. coli + RvD1 + ciprofloxacin


SPMs are tissue protective

in inflammatory disease

M Arita et al. PNAS 2005Resolvin E1, an endogenous lipid mediator derived from omega‐3 eicosapentaenoic acid, protects against 2,4,6‐trinitrobenzene sulfonic acid induced colitis.



Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice. Tani, et al. FASEBJ 2014.

Specialized proresolving mediators enhance human B cell differentiation to antibody‐secreting cells. J. Immunol. 189, 2012. Ramon S, Gao F, Serhan CN, Phipps RP.

The specialized proresolving mediator 17‐HDHA enhances the antibody‐mediated immune response against influenza virus: A new class of adjuvant? Ramon S, et al J. Immunol. 2014 Nov 12.

Resolution-type eosinophils

PD1, RvD1, LXA4

Lymph node

Increased B‐cell maturation and antigen‐specific antibody formation

B cell

Macrophage

CXCL13

+

migration to draining lymph node

17‐hydroxy‐DHA

+

SPMs promote adaptive immunity

SPM formation upon oral intake of its precursors EPA and DHA

Increase of EPA‐derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long‐chain omega‐3 PUFA. Prostaglandins Other Lipid Mediat. 2014. Schuchardt JP, Schneider I, Willenberg I, Yang J, Hammock BD, Hahn A, Schebb NH.

Identification and signature profiles for pro‐resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol. 307, 2014. Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN.


Formation of lipid mediators from a single oral dose of EPA/DHA

Activation of whole blood phagocytic activity after a single oral dose of EPA/DHA


‐ Transcellular biosynthesis permits local biosynthesis under specific conditions (context‐dependent cell‐cell interactions)

‐ Receptor‐mediated anti‐inflammatory and resolution‐activating actions

‐ Endogenous agonists for regulating the inflammatory response

Omega‐3‐derived lipid mediators in the inflammatory response

The lipoxin analogue ATLa stops leukocyte infiltration in zymosan A‐stimulated peritonitis

Inhibitio

n of leukocyte

infiltration (%

)

Lipid mediators have oral bio‐availability and/or systemic actions

Stable lipoxin analogs

COOCH3

OHHO

OOH

F

ATLa 15‐epi‐16‐(p‐fluoro)‐phenoxy‐LXA4‐methyl ester

Bannenberg et al. Br. J. Pharmacol. 2004Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration.


Dose ATLa(ng)

1.0 10 100

Gavage

0

20

40

60

80

Dose ATLa(ng)

10 100 1000

Intravenous

ATLa LXA4 LXB4

Gavage

Dose 100 ng

Acknowledgments:

Organizers of Food Matters Live

The Serhan laboratory ‐ Centre for Experimental Therapeutics & Reperfusion Injury,Brigham & Women’s Hospital / HMS ‐ Boston (MA), USA

Solutex GC (Madrid, Spain)

GOED – Global Organization for EPA and DHA


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