J Phys Fitness Sports Med, 2(4): 487-492 (2013)DOI: 10.7600/jpfsm.2.487

JPFSM: Short Review Article

Mechanisms of chronic inflammation improvementby exercise: Focus on immune response of local tissue

Noriaki Kawanishi1*, Hiromi Yano2, Tsubasa Mizokami3 and Katsuhiko Suzuki4

Received: August 31, 2013 / Accepted: September 9, 2013

Abstract Obesity is associated with the pathogenesis of chronic inflammatory diseases, such as type II diabetes and nonalcoholic steatohepatitis, which in turn have been attributed to the chronic inflammation in visceral adipose tissue and liver. The innate immune system via mac-rophages, neutrophils and lymphocytes is related to development of chronic inflammation. Ex-ercise has anti-inflammatory effects and may prevent the development of chronic inflammatory diseases. To elucidate mechanisms of chronic inflammation improvement and/or prevention in the local tissue due to exercise is important to ensure development of effective exercise therapy. This review provides information to elucidate the molecular mechanisms from the perspective of immune regulation on the improvement of chronic inflammation due to exercise.Keywords : regular exercise, obesity, chronic inflammation, immune system

Introduction

In developed countries, metabolic syndrome is increas-ing rapidly due to changes in lifestyle such as inactivity and overeating. It is clear that inadequate physical activity can result in obesity, type 2 diabetes, atherosclerosis and nonalcoholic steatohepatitis (NASH). However, physical activity effectively prevents the development of metabolic syndrome1). Therefore, interventions including exercise and nutrition that improve metabolic syndrome constitute important therapeutic strategies. Recently, the innate immune system via macrophages and lymphocytes has been associated with the develop-ment of chronic inflammation, which is correlated with inducing insulin resistance, dyslipidemia and hyperten-sion2). Chronic inflammation is also associated with local inflammatory response in adipose tissue and liver3). Tis-sue resident macrophages release inflammatory cytokines and reactive oxygen species, which induce systemic inflammation4). Obese patients display high plasma lev-els of pro-inflammatory cytokines and oxidative stress biomarkers5). Exercise has anti-inflammatory effects and may prevent the development of chronic inflammatory diseases6). Regular exercise appears to reduce the plasma concentrations of inflammatory mediators such as pro-inflammatory cytokines and reactive oxygen species in obese patients. Therefore, increasing physical activity

can lead to a reduction in systemic inflammation via a decrease in pro-inflammatory mediator secretion. To elu-cidate the mechanisms of chronic inflammation improve-ment and/or prevention in the local tissue due to exercise is important for the development of an effective exercise prescription. This review provides that information to elu-cidate the molecular mechanisms from the perspective of immune regulation of the improvement in chronic inflam-mation due to exercise.

Effects of exercise on local tissue inflammation in obesity

Obesity is associated with the pathogenesis of chronic inflammatory diseases, which in turn has been largely at-tributed to chronic local tissue inflammation in visceral adipose tissue7). Several inflammatory mediators such as pro-inflammatory cytokines and chemokines are secreted from adipocytes and macrophages8). Several important cy-tokines and chemokines are implicated in tissue dysfunc-tion, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1. Pro-inflammatory cytokines such as TNF-α is known to induce adipocyte death through activation of apoptosis signaling9). Moreover, chemokines such as MCP-1 and macrophage inflammatory protein (MIP)-1, are respon-sible for activating and infiltrating macrophages in tissue area, which contributes to local tissue inflammation10). There is evidence that the expression of pro-inflammatory cytokines and chemokines in adipose tissue and liver are *Correspondence: kawanishinoriaki@hs.hokudai.ac.jp

1 Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Sapporo, Hokkaido 060-0812, Japan2 Department of Health and Sports Science, Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki, Okayama

701-0193, Japan3 Graduate School of Sport Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama 359-1192, Japan4 Faculty of Sport Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama 359-1192, Japan

488 JPFSM : Kawanishi N, et al.

increased in obese humans and mice11,12). These inflamma-tory proteins can be released into the circulation, resulting in chronic systemic low-grade inflammation, which is as-sociated with insulin resistance. Thus, these mediators are a marker for evaluating the inflammatory state of local tissue induced by obesity. Several recent studies have examined the effects of ex-ercise on reducing adipose tissue inflammation in obese mice. In mice on a high fat diet for 16 weeks, endurance exercise has been shown to reduce gene expression of inflammatory markers (such as TNF-α and MCP-1) in visceral adipose tissue and liver13,14). Vieira et al.15) also reported that 12 weeks of endurance exercise decreased gene expression of TNF-α and MCP-1 in the visceral adipose tissue in obese mice. Moreover, several studies have shown that gene expression of TNF-α and MCP-1 in visceral adipose tissue was reduced in voluntary exercis-ing mice, even when the mice continued to consume a high fat diet16,17). Similarly, in humans, intermittent high-intensity exercise for two weeks reduced IL-6 protein lev-els in subcutaneous adipose tissue of obese individuals18). Furthermore, a 15-week lifestyle intervention incorporat-ing exercise and diet was associated with decreased gene expression of IL-6, TNF-α, and MCP-1 in subcutane-ous adipose tissue of obese individuals19). Also, obesity-induced muscle inflammation was reported20). However, 12 weeks of combined endurance and resistance exercise resulted in decreased TNF-α and IL-6 gene expression in skeletal muscle of obese individuals21). In addition, Jung et al.22) also reported that high expressions of TNF-α and IL-6 in skeletal muscle after high-fat diet were normal-ized after 3 weeks of endurance exercise. Taken together, these findings provide evidence to support that regular exercise reduces the development of local tissue inflam-mation associated with obesity. Recently, it was shown that weight loss by caloric re-striction and exercise resulted in improvement of adipose tissue inflammation23). Exercise appears to be an impor-tant intervention for decreasing weight gain, but the con-tribution of weight loss from exercise in the reduction of adipose tissue inflammation is unclear. Indeed, data from several studies suggest that regular endurance exercise-induced weight loss resulted in a decrease in local tissue inflammation22). However, it was shown that regular en-durance exercise in obese mice decreased gene expression of pro-inflammatory cytokines in adipose tissue and liver without loss of weight14,24). Therefore, the reduction of in-flammation in both adipose tissue and liver might directly depend on regular exercise.

Preventive effect of exercise on chronic inflammatory disease

NASH is an important component of metabolic syn-drome, which is characterized by insulin resistance, dys-lipidemia, and hypertension. The innate immune system

plays a key role in the development of NASH25). Kupffer cells (also known as Browicz-Kupffer cells and stellate macrophages), hepatic resident macrophages, produce various pro-inflammatory cytokines and reactive oxygen species, which enhance hepatic inflammation and fibro-sis26). Chronic exercise may prevent or reduce the severity of NASH27). In patients with NASH, physical activity lev-el was negatively associated with the state of fibrosis28); and chronic exercise-reduces the serum aminotransferase levels as a marker of hepatic injury29). Moreover, regular exercise training also improves serum aminotransferase levels and hepatic steatosis in obese mice30,31). However, the mechanism of how exercise training attenuates the de-velopment of hepatic inflammation and fibrosis remains unclear. A very recent study found that regular exercise drasti-cally attenuates hepatic inflammation and fibrosis, indi-cating the positive effects of exercise on improvement of NASH. In the experimental model frequently used to induce NASH (high-fat diet and high-fructose water feed-ing), it was shown that the TNF-α protein content in liver was increased after a 16-week feeding, while 16 weeks of endurance exercise induced a significant decrease in hepatic TNF-α content24). Similarly, Jung et al.21) reported that hepatic protein levels of IL-6 and TNF-α were elevat-ed after a high-fat diet, but reduced after 3 weeks of en-durance exercise. Furthermore, we showed that 16 weeks of endurance exercise induced decreases in collagen de-position and mRNA levels of fibrogenic markers such as collagen type 1 α and tissue inhibitor of metalloproteinase (TIMP)-124). Also, in a human study, Promrat et al.32) dem-onstrated that 48 weeks of exercise reduced steatosis and the inflammatory score in NASH patients. Taken together, these findings suggest that regular endurance exercise may prevent or improve NASH. Interestingly, recent studies observed that regular endurance exercise in diet-induced obese mice attenuated macrophage infiltration in the liver21,24). A recent study proposed that macrophages play pathogenic roles in NASH, because macrophage-depleted mice showed both lower hepatic inflammation and fibrosis than normal mice33). Collectively, our find-ings indicate that the reduction in hepatic inflammation and fibrosis by regular endurance exercise is associated with suppression of macrophage infiltration.

Changes in the number and subset composition of leu-kocytes

Adipose tissue consists of a variety of cell types includ-ing adipocytes, endothelial cells, and immune cells. Re-cently, it has been shown that the innate immune response mainly mediated by macrophages and lymphocytes is key to the inflammatory process in adipose tissue34). Recent studies showed enhanced infiltration of macrophages and lymphocytes in high-fat diet-induced obesity in mice35,36). Our studies and those of others showed that regular en-

489JPFSM : Exercise and chronic local/systemic inflammation

durance exercise in obese mice reduced mRNA levels of macrophage markers such as F4/80 in adipose tissue13,15). Furthermore, we also analyzed the characteristics of the cell types in adipose tissue by flow cytometry, and found that 16 weeks of endurance exercise in diet-induced obe-sity in mice decreased the cell number of macrophages and lymphocytes in visceral adipose tissue. Similarly, Xu et al.37) reported that 8 weeks of endurance exercise also acts to decrease macrophage contents in the visceral adipose tissue in obese mice. Interestingly, macrophage activation has been operationally classified into two separate polarization states38). M1 macrophages produce inflammatory cytokines such as TNF-α and IL-6. In con-trast, M2 macrophages produce IL-10, which suppresses inflammation and oxidative stress. Lumeng et al.39) report-ed that mice with high-fat diet-induced obesity show a phenotypic switching from M2 macrophages to M1 mac-rophages in adipose tissue. On the other hand, cytotoxic CD8+ T cells produce chemokines such as MCP-1 and MIP-1α, which modulate the activation and infiltration of macrophages in adipose tissue34). In contrast, helper CD4+ T cells produce cytokines such as IL-4 and IL-10, which suppress macrophage infiltration40). Therefore, M1 macrophages and CD8+ T cells have been shown to play critical roles in the associated adipose tissue inflamma-tion. Wasinski et al.41) reported that the number of CD8+ T cells in adipose tissue decreased after 6 weeks of endur-

ance exercise. We also found that 16 weeks of endurance exercise decreased the cell number of M1 macrophages and CD8+ T cells, and changed the ratio of macrophage and T cell subsets in obese adipose tissue14). In contrast to the decreased ratio of M1 macrophages and CD8+ T cells, the ratio of M2 macrophages and CD4+ T cells remained unchanged after 16 weeks of endurance exercise. Interest-ingly, this phenomenon was unique to visceral adipose tissue, because the macrophages and T cell subsets in the spleen and blood leukocytes did not change with 16 weeks of endurance exercise training. These results indi-cate that regular endurance exercise may improve adipose tissue inflammation by changing the number and subset composition of leukocytes (Fig. 1).

Future prospects

Aberrant action of the innate immune response, mainly by macrophages, is important for development of an inflammatory state of local tissue. Interestingly, it is re-ported that the adaptive immune system plays a key role in the development of chronic inflammation in visceral adipose tissue in addition to the innate immune system42). Recently, several studies have investigated the role of spe-cific subsets of T cells or B cells in adipose tissue. CD4+ helper T cell activation has been operationally defined as several separate polarization states such as Th17 and reg-

Fig. 1 Mechanisms of the anti-inflammatory effects of regular exercise. Physical inactivity and overeating lead to an infiltration of inflammatory macrophages (M1) and CD8+ T cells into visceral

adipose tissue. M1 macrophages and CD8+ T cells release pro-inflammatory mediators such as TNF-α, IL-6 and MCP-1, which increase risk for local and systemic chronic inflammation. Regular exercise induces change in the number and subset composi-tion of macrophages and T cells, reducing the ratio of M1 to M2 macrophages and the ratio of CD8+ T cells to CD4+ T cells. M2 macrophages release anti-inflammatory mediators such as IL-4 and IL-10, which leads to a reduction in inflammation. Thus, regular exercise attenuates the development of diabetes and NASH.

TNF, tumor necrosis factor; IL-6, interleukin-6; NASH, nonalcoholic steatohepatitis.

M1 macrophage

M2 macrophage

CD8+ T cell

CD4+ T cell

Regular Exercise

Lean

SedentaryIncreased risk for disease

(NASH, Diabetes)

Local/Systemic inflammation

Anti-inflammation effect Reduced risk for disease

Infiltration of macrophage and T cells Pro-inflammatory cytokine production

(TNF- , IL-6)

ObesityInfiltration of macrophage and T cells Ratio of M1 to M2 macrophages Ratio of CD8+ T cells to CD4+ T cells Pro-inflammatory cytokine production

M

M

Necrotic adipocyte

LipolysisCrown-like structure

490 JPFSM : Kawanishi N, et al.

ulatory T cells, which are associated with the induction of adipose tissue inflammation43). Th17 cells were increased, while regulatory T cells which decreased in adipose tissue after feeding a high-fat diet44,45). Th17 cells increase and these cells produce MCP-1, which induces macrophage infiltration and adipose tissue inflammation46). In con-trast, regulatory T cells have also been shown to inhibit macrophage activation47). Furthermore, obesity has been shown to increase infiltration of mature B cells into vis-ceral adipose tissue. Mature B cells also produce patho-genic IgG antibodies that cause the activation of T cells and macrophages48). Thus, these results show that Th17, regulatory T cells and B cells potentiate macrophage and T cell polarization, which promote obesity-related local/systemic chronic inflammation (Fig. 2). Further work will be required to determine whether regular exercise affects the adaptive immune system via altering CD4+ helper T cells and B cell polarization.

Fig. 2 Development of obesity-related chronic inflammation via innate immune and adaptive immune systems. In early obesity, there is a shift in T cell populations towards Th17 cell polarization, and B cell infiltration of visceral adipose

tissue. Helper T cells and B cells increase the recruitment of M1 macrophages and CD8+ T cells into visceral adipose tissue, and promote the aberrant action of the innate immune system.

TNF, tumor necrosis factor; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; MIP, macrophage inflam-matory protein.

Acknowledgments

The authors would like to thank Dr. Cecilia Shing for the Eng-lish editing of this manuscript. This study was partly supported by grants from the Ministry of Education, Culture, Sports Science and Technology of Japan, Grant-in-Aid for the Global COE Pro-gram “Sport Science for the Promotion of Active Life”, Scientific Research (A) 23240097, and a grant-in-aid from the Japan Soci-ety for the Promotion of Science Fellows.

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