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The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease
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Nature Reviews Immunology, advance online publication, Published online 5 August 2011 Michael Gleeson1, Nicolette C. Bishop1, David J. Stensel1, Martin R. Lindley1, Sarabjit S. Mastana1 & Myra A. Nimmo1
Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise - both acute and chronic - exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease.
The prevalence of obesity continues to rise worldwide and is being accompanied by a proportional increase in the incidence of other medical conditions, such as type 2 diabetes mellitus (T2D). Such conditions are associated with derangements in the interplay between metabolic and immune processes (immunometabolism)1. Moreover, obesity is associated with cardiovascular disease (CVD), chronic obstructive pulmonary disease, colon cancer, breast cancer, dementia and depression. Inflammation appears to be aetiologically linked to the pathogenesis of all of these conditions2, 3, 4, 5, 6, and the development of a chronic low-grade inflammatory state has been established as a predictor of risk for several of them7. This inflammatory state is indicated by elevated levels of circulating inflammation markers, such as interleukin-6 (IL-6), tumour necrosis factor (TNF) and C-reactive protein (CRP). Importantly, physical inactivity and sedentary behaviour also increase the risk of these conditions5, 8, 9, 10, 11. An inactive lifestyle leads to the accumulation of visceral fat, and this is accompanied by adipose tissue infiltration by pro-inflammatory immune cells, increased release of adipokines and the development of a low-grade systemic inflammatory state4. This low-grade systemic inflammation has, in turn, been associated with the development of insulin resistance, atherosclerosis, neurodegeneration and tumour growth6, 7, 8 (Fig. 1). Exercise has anti-inflammatory effects, and therefore, in the long term, regular physical activity can protect against the development of chronic diseases8, 9, 10, 11 (Table 1). In addition, exercise can be used as a treatment to ameliorate the symptoms of many of these conditions, and thus the concept that 'exercise is medicine'12 (Box 1) is increasingly promoted in the hope that the general population can be persuaded to partake in more physical activity.
Obviously exercise increases energy expenditure and burns off some of the body fat that would otherwise accumulate in individuals who consume more dietary energy than they need. In this sense, exercise reduces the risk of developing obesity and excessive adiposity. Regular exercise also promotes cardiovascular health, as it improves the blood lipid profile by decreasing the concentration of plasma triglycerides and low-density lipoprotein (LDL) particles and increasing the concentration of protective high-density lipoprotein (HDL) cholesterol13. These beneficial alterations in plasma lipids are presumed to limit the development of atherosclerosis. However, the protective effect of a physically active lifestyle against chronic inflammation-associated diseases (Table 1) may additionally be ascribed to an anti-inflammatory effect of exercise14, 15, 16. This may be mediated not only via a reduction in visceral fat mass (with a subsequent decreased production and release of pro-inflammatory adipokines) but also by induction of an anti-inflammatory environment with each bout of exercise15, 16. In this Review, we explain the possible mechanisms by which exercise exerts its anti-inflammatory effect and briefly discuss the implications for the use of exercise as a medicine in the prevention and treatment of chronic disease. We also consider the impact of intensive training on infection risk for endurance athletes.
Anti-inflammatory effects of exercise
Recent reviews on the anti-inflammatory effects of exercise15, 16, 17 have focused on three possible mechanisms: the reduction in visceral fat mass; increased production and release of anti-inflammatory cytokines from contracting skeletal muscle (such molecules are termed myokines15, 18); and reduced expression of Toll-like receptors (TLRs) on monocytes and macrophages17 (with subsequent inhibition of downstream responses, such as the production of pro-inflammatory cytokines and the expression of MHC and co-stimulatory molecules)19. In addition, mouse studies have revealed that the anti-inflammatory effects of exercise also rely on other mechanisms, such as the inhibition of monocyte and macrophage infiltration into adipose tissue20 and the phenotypic switching of macrophages within adipose tissue20. Although these types of analysis are difficult to conduct in humans, analysis of human peripheral blood following exercise has revealed a reduction in the circulating numbers of pro-inflammatory monocytes21 and an increase in the circulating numbers of regulatory T cells (TReg cells)22, 23. This suggests that such mechanisms may also be involved in the anti-inflammatory effects of exercise in humans. However, there are some limitations in the study of the immunological effects of exercise (both acute and chronic) in humans; these types of study and their limitations are summarized in Box 2.
Reduction in visceral fat mass. The accumulation of body fat - particularly in the abdomen, liver and muscles - is associated with increased all-cause mortality24 and the development of T2D25, CVD26, dementia27 and several cancers28. The expansion of the adipose tissue results in increased production of pro-inflammatory adipokines, such as TNF, leptin, retinol-binding protein 4, lipocalin 2, IL-6, IL-18, CC-chemokine ligand 2 (CCL2; also known as MCP1), CXC-chemokine ligand 5 and angiopoietin-like protein 2 (Ref. 4). Conversely, the amounts of anti-inflammatory cytokines (for example, adiponectin and secreted frizzled-related protein 5) are reduced4. This leads to the development of a persistent state of low-grade systemic inflammation29.
Regular exercise can reduce waist circumference and cause considerable reductions in abdominal and visceral fat, even in the absence of any loss of body weight, in both men and women regardless of age30. Furthermore, regular exercise results in higher circulating levels of adiponectin and lower levels of several circulating pro-inflammatory adipokines, including IL-6, TNF, retinol-binding protein 4 and leptin31, 32, 33. It is not known whether the levels of the other adipokines (mentioned above) are reduced in the blood following exercise, and further research is needed to address this. So, increased physical activity can bring about a reduction in systemic inflammation29 via a decrease in pro-inflammatory adipokine secretion, which is a direct result of lowering the amount of fat stored in abdominal depots. Release of IL-6 from contracting muscle. At rest, approximately 30% of circulating IL-6 arises from the adipose tissue34, but only about 10% of this can be attributed to the adipocytes35 with the remainder coming mostly from adipose tissue-resident macrophages. Other sources of circulating IL-6 include blood leukocytes (predominantly monocytes), the brain and the liver. During and following exercise of sufficient load, the active skeletal muscle markedly increases both cellular and circulating levels of IL-6 (Ref. 36). With prolonged exercise (over 2.5 hours), IL-6 levels can increase over 100-fold, although more modest increases are reported with exercise of a shorter duration37. Increases have also been noted using intermittent exercise protocols of relatively short duration38. The increase in IL-6 during exercise is transient, normally returning to resting levels within 1 hour after exercise. The plasma IL-6 concentration increases exponentially with exercise duration, and a major stimulus of its synthesis and release appears to be a fall in muscle glycogen content39, 40. Increases in intracellular calcium levels and increased formation of reactive oxygen species are also capable of activating transcription factors that are known to regulate IL-6 synthesis37.
The transient rise in circulating IL-6 during exercise appears to be responsible for a subsequent rise in circulating levels of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist (IL-1RA), and it also stimulates the release of cortisol from the adrenal glands41. This is demonstrated with the observation that intravenous infusion of IL-6 mimics the acute anti-inflammatory effects of a bout of exercise, both with regard to elevation of plasma IL-10, IL-1RA and cortisol41 and with regard to suppression of endotoxin-stimulated increases in TNF levels42.
IL-1RA is secreted mainly by monocytes and macrophages and inhibits the pro-inflammatory actions of IL-1ß43. IL-10 is known to be produced primarily by TReg cells but also by T helper 2 (TH2) cells, TH1 cells, TH17 cells, monocytes, macrophages, dendritic cells (DCs), B cells and CD8+ T cells44. Irrespective of the cellular source, the principal function of IL-10 appears to be the downregulation of adaptive immune responses45 and minimization of inflammation-induced tissue damage. In detail, IL-10 downregulates the expression of MHC molecules, intercellular adhesion molecule 1 (ICAM1) and the co-stimulatory molecules CD80 and CD86 on antigen-presenting cells, and it has also been shown to promote the differentiation of DCs expressing low levels of MHC class II, CD80 and CD86 (Ref. 44). In addition, IL-10 downregulates or completely inhibits the expression of several pro-inflammatory cytokines and other soluble mediators, thereby further compromising the capacity of effector T cells to sustain inflammatory responses44, 45. Thus, IL-10 is a potent promoter of an anti-inflammatory state.
Circulating levels of IL-10 are lower in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance46. Moreover, IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines and the deleterious effects of these cytokines on insulin signalling and glucose metabolism46.
The action of IL-6 and the subsequent cascade of anti-inflammatory cytokines is not the only mechanism responsible for the health benefits that are associated with exercise, as elevations of IL-6 do not occur with short durations of low to moderate intensity exercise37 despite the known health benefits (for example, reduced risk of heart disease) associated with only very moderate increases in physical activity above that of a sedentary lifestyle47, 48.
Increased levels of circulating cortisol and adrenaline. Secretion of the adrenal hormones cortisol and adrenaline is increased during exercise owing to activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system (SNS). Impulses from the motor centres in the brain as well as afferent impulses from working muscles elicit an intensity-dependent increase in sympathoadrenal activity. These neural signals also induce the release of some hypothalamic releasing factors, which increase the secretion of certain pituitary hormones, including adrenocorticotropic hormone (ACTH)49. Increased SNS activity stimulates the release of the catecholamines adrenaline and noradrenaline from the adrenal medulla within seconds of the onset of exercise, and ACTH stimulates cortisol secretion from the adrenal cortex within minutes. These hormonal responses usually precede the rise in circulating concentrations of cytokines, and the magnitude of the elevations in plasma cortisol and adrenaline levels is related to the intensity and duration of exercise49. Cortisol is known to have potent anti-inflammatory effects50, and catecholamines downregulate the lipopolysaccharide (LPS)-induced production of cytokines (including TNF and IL-1ß) by immune cells51. Cortisol secretion is also augmented by the aforementioned rise in circulating IL-6 from working skeletal muscle41. Thus, hormones, myokines and cytokines all contribute to the anti-inflammatory effect of exercise (Fig. 2).
Inhibition of macrophage infiltration into adipose tissue. Macrophages and T cells that infiltrate adipose tissue in obesity are known to regulate the adipose tissue's inflammatory state52, 53. Thus, the migration of peripheral blood mononuclear cells (PBMCs) towards sites of inflammation, including adipose tissue and damaged vascular endothelium, is central to the development of sustained tissue inflammation54, 55, 56, 57. It has been suggested that the increased size of the adipocytes, rather than an overall increase in adipose tissue mass, triggers macrophage infiltration58, and it has been speculated that the recruitment of macrophages may be stimulated by the chemokines CCL2 and CCL3 (also known as MIP1α)55, 59.
Exercise may limit the movement of PBMCs into inflamed adipose tissue, although there is little evidence to support this at present20. The migration of PBMCs from the circulation into the tissues is a tightly regulated process. It requires a gradient of chemokines that are released from the inflamed tissue (including from immune cells residing within the tissue), the expression of complimentary chemokine receptors on PBMCs and the expression of adhesion molecules on both immune and endothelial cells. Acute bouts of exercise reduce T cell migration towards the supernatants from human airway epithelial BEAS-2B cells infected with rhinovirus in a manner that is independent of any involvement of adhesion molecules or exercise-induced elevations of cortisol or catecholamines60. However, it is known that the stress induced by acute exercise results in the release of chemokines from multiple sources into the circulation61, and sustained exposure of PBMCs to physiological concentrations of chemokines (including CCL2) results in chemokine receptor internalization62. This is thought to serve as a negative feedback mechanism to reduce migration and thereby terminate the accumulation of PBMCs in inflamed tissue. It is possible, therefore, that an active lifestyle causes repeated short-lasting elevations in plasma levels of chemokines, which act over time to downregulate expression of their receptors on PBMCs and restrict migration of these cells towards adipose tissue. However, this potential mechanism needs to be explored further in humans. Conversely, there is some evidence from murine studies in support of the concept that exercise inhibits the release of chemokines from adipose tissue and in this way reduces macrophage infiltration, although whether this occurs in humans is not clear54, 63.
In a mouse model, training was reported to decrease the tissue expression of ICAM1 (Ref. 20), which has a role in the adhesion of inflammatory cells to vascular endothelium, the extracellular matrix and epithelium, and also mediates interactions between T cells and target cells. Signal transduction downstream of these interactions leads to T cell activation, proliferation, cytotoxicity and cytokine production. ICAM1 expression is known to be increased in obesity in humans64, and blocking ICAM1 in obese mice prevented macrophage infiltration into adipose tissue65. Moreover, circulating ICAM1 levels were reduced in patients with T2D following 6 months of progressive aerobic exercise training, without changes in body mass or waist circumference66. Obviously, further studies in humans are required to ascertain the effect of exercise training on ICAM1 expression in adipose tissue, but ICAM1 might also have a role in the exercise-induced reduction of macrophage infiltration into adipose tissue. Macrophage activation results in two separate polarization states: M1 and M2 (Ref. 67). M1-type macrophages produce TNF, IL-6 and nitric oxide, whereas M2-type macrophages produce anti-inflammatory cytokines and arginase. Therefore, M1-type macrophages induce an inflammatory state and M2-type macrophages subdue inflammation in adipose tissue. Inflamed adipose tissue appears to be associated with a preferential recruitment of M1-type macrophages and/or a phenotypic switch of adipose tissue macrophages towards the M1 phenotype68. Therefore, it is possible that the attenuated inflammatory state of adipose tissue that is associated with chronic exercise training occurs by both suppression of macrophage infiltration and acceleration of phenotypic switching from M1- to M2-type macrophages. Indeed, a recent study in mice fed a high-fat diet to induce obesity provided some evidence that exercise training induces this phenotypic switching from M1- to M2-type macrophages in adipose tissue and inhibits M1-type macrophage infiltration into adipose tissue20. However, studies in humans are still scarce.
Downregulation of TLR expression. TLRs are highly conserved transmembrane proteins that have an important role in the detection of microbial pathogens and in the recognition of endogenous danger signals released following tissue damage, such as heat shock proteins69. Activation of TLR signalling results in increased expression and secretion of pro-inflammatory cytokines and thus has an important role in mediating systemic inflammation70. Evidence is now emerging that TLRs may be involved in the link between a sedentary lifestyle and inflammation and disease. Exercise training studies and cross-sectional comparisons between physically active and inactive subjects have shown that blood monocytes from physically active individuals have a reduced inflammatory response to endotoxin stimulation in vitro. These cells also have decreased TLR4 expression (at both cell surface protein and mRNA levels)17, 19, which is associated with decreased inflammatory cytokine production71.
Following an acute, prolonged bout of strenuous exercise, the expression of TLR1, TLR2 and TLR4 on monocytes is decreased for at least several hours19, 72, 73. Prolonged exercise also results in a decreased induction of co-stimulatory molecules and cytokines following stimulation with known TLR ligands, such as LPS and zymosan71. Whether this reduction in cell surface expression of TLRs is due to downregulation of TLR gene expression, shedding of TLRs from the cell surface or re-internalization by the cell remains to be established. The precise physiological stimulus that mediates an exercise-induced decrease in cell surface TLR expression is not known; however, several possible signals have been implicated, including anti-inflammatory cytokines, stress hormones and heat shock proteins19.
The evidence discussed above points to a downregulation of TLR expression and subsequent downstream inflammatory signalling cascades with acute exercise. However, as prolonged exercise increases lipolysis and elevates plasma levels of free fatty acids, which are ligands for TLR2 and TLR4 (Ref. 74), it might be surmised that exercise could induce inflammatory cascades via activation of TLRs. However, there is no direct evidence for this, and LPS-stimulated cytokine production by blood monocytes is clearly reduced, not increased, following prolonged exercise42, 71, 75.
Reduced numbers of pro-inflammatory monocytes in blood. There are two main populations of monocytes: classical (CD14hiCD16-) and non-classical (CD14lowCD16+ or CD14hiCD16+). These subsets differentially express cell surface TLR4, with the inflammatory CD14lowCD16+ monocytes expressing 2.5 times as much cell surface TLR4 as the other populations76. Despite constituting only 10% of the total monocyte population, inflammatory monocytes contribute significantly to the inflammatory potential of the monocyte pool as a whole77. The percentage of circulating inflammatory monocytes is elevated in patients with rheumatoid arthritis78, CVD79 and T2D80, and it has been suggested that inflammatory monocytes play a significant role in the pathogenesis of several diseases linked to inflammation. Transient increases in the numbers of inflammatory monocytes have been observed after a single, acute bout of intense exercise81, followed by a rapid return to baseline numbers during recovery. However, regular exercise appears to reduce the proportion of inflammatory monocytes in the circulation in the resting state. For example, a cross-sectional comparison of healthy, physically inactive elderly men and women with an age-matched physically active group indicated that sedentary people have a twofold higher percentage of circulating inflammatory monocytes21. Furthermore, 12 weeks of regular exercise training markedly reduced the percentage of inflammatory monocytes in the inactive group to the level of the active group, and endotoxin-stimulated TNF production was reduced substantially after the training intervention. Based on previous reports that glucocorticoid therapy selectively depletes CD14lowCD16+ monocytes82, it is interesting to speculate that exercise-induced transient spikes in plasma cortisol levels may have a role in reducing the number of CD14lowCD16+ monocytes.
Of course, a reduction in the number of inflammatory monocytes in the blood could also be indicative of increased monocyte infiltration into the tissues or migration of pro-inflammatory monocytes into the lymphoid organs83. However, this notion is not supported by murine studies that demonstrate reduced leukocyte infiltration and inflammation in dermal wound sites after exercise84. Further analysis and functional studies are needed in humans to confirm that exercise reduces the numbers of pro-inflammatory monocytes and that this contributes to its anti-inflammatory effects.
Increased circulating numbers of regulatory T cells. CD4+CD25+ TReg cells specifically express the transcription factor forkhead box P3 (FOXP3)85 and suppress immune responses. Studies show that the depletion of these cells can lead to autoimmunity and enhances the immune response to foreign antigens86, 87, 88, 89. Interestingly, one study showed that a 12-week programme of Tai Chi Chuan exercise induced a substantial increase in circulating TReg cell numbers22. The production of the TReg cell-derived cytokines transforming growth factor-ß (TGFß) and IL-10 in response to in vitro antigenic stimulation was also markedly increased in PBMCs isolated after this exercise programme. Furthermore, a study of patients with T2D showed that regular Tai Chi Chuan exercise altered the balance between TH1, TH2 and TReg cell subsets by increasing FOXP3 but not TGFß expression90.
In a study that used a running mouse model, the responses of circulating TReg cells to moderate- or high-intensity exercise training were examined. Only the high-intensity training resulted in increases in TReg cell numbers, and it was also associated with reduced pro-inflammatory and increased anti-inflammatory cytokine expression23. Intriguingly, these findings imply that high-intensity exercise training might be more beneficial than moderate-intensity training in reducing the risk of chronic cardiovascular and metabolic diseases, as a result of its anti-inflammatory effects. This notion is supported by another recent study that showed that a combination of high-intensity aerobic plus resistance exercise training, in addition to daily physical activity, is required to achieve a significant anti-inflammatory effect in T2D patients91.
Other factors. During acute exercise, there is a marked increase in the circulating levels of growth hormone, prolactin, heat shock proteins and other factors that have immunomodulatory effects by influencing leukocyte trafficking and functions92. Thus, these molecules may also contribute to the anti-inflammatory effects of exercise.
Taken together, these findings suggest that each bout of exercise induces an anti-inflammatory environment. Various mechanisms can contribute to this (Fig. 2), and it seems likely that their relative importance will vary depending on the frequency, intensity and duration of the exercise performed. For low-intensity exercise, such as brisk walking, it is likely that the control of body fat is the most important mechanism, but for short periods of high-intensity exercise and prolonged moderate-intensity exercise the other anti-inflammatory effects may have an increasingly important role.
The elite athlete paradox
Although regular moderate-intensity exercise is associated with a reduced incidence of upper respiratory tract infection compared with a completely sedentary state93, 94, the long hours of hard training that elite athletes undertake appears to make them more susceptible to upper respiratory tract infections11, 95, 96, 97, 98. This is probably attributable to the anti-inflammatory effects of exercise inducing a degree of immunosuppression11, 98, although other factors - such as psychological stress, disturbed sleep and negative energy balance - may contribute to immunosuppression in elite athletes98. An increased risk of minor infections may be the (small) price to be paid for the long-term health benefits of regular exercise at high dosage. A recent murine study indicated that intensive exercise training results in an increased anti-inflammatory cytokine (IL-10) response to antigen exposure23. Moreover, a study on human endurance athletes revealed that whole blood cultures from athletes who were prone to illness during a 4-month period of winter training produced four times as much IL-10 following antigen stimulation as blood cultures from athletes who remained illness-free during the same period99. There is now extensive evidence from both murine and human studies that IL-10 production usually imposes some limits on the effectiveness of pathogen-specific immune responses, especially innate immunity and adaptive TH1 cell responses100, 101. These studies suggest that very high training loads induce an anti-inflammatory state that is sufficient to increase the risk of minor infections.
Conclusions and remaining questions
Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases (Table 1), in part because exercise exerts anti-inflammatory effects. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. Various mechanisms may contribute to the generation of this anti-inflammatory environment, including: increased release of cortisol and adrenaline from the adrenal glands; increased production and release of IL-6 and other myokines from working skeletal muscle; reduced expression of TLRs on monocytes and macrophages (with subsequent inhibition of downstream pro-inflammatory cytokine production); inhibition of adipose tissue infiltration by monocytes and macrophages; phenotypic switching of macrophages within adipose tissue; a reduction in the circulating numbers of pro-inflammatory monocytes; and an increase in the circulating numbers of TReg cells. These anti-inflammatory effects of exercise are also likely to be responsible for the partial immunosuppression that makes elite athletes more susceptible to common infections.
At present, we do not know the relative importance of these different anti-inflammatory mechanisms, although it seems likely that this will depend on the mode, frequency, intensity and duration of the exercise performed. Intuitively, we might expect IL-6 to assume greater relative importance when the exercise is prolonged and glycogen-depleting, whereas catecholamine-mediated effects are likely to assume greater importance with shorter duration, high-intensity exercise. High training loads may be needed to increase circulating numbers of TReg cells and maximize the anti-inflammatory effects, but possibly at the cost of a small increase in infection risk. Further research should establish the mode, intensity and duration of exercise required to optimize the anti-inflammatory effects, and it still remains to be established whether exercise is always useful as a therapy for the treatment of patients with inflammation-associated disorders. Furthermore, we still need to determine the independent contribution of an exercise-induced reduction in visceral fat (versus other exercise-induced anti-inflammatory mechanisms) in reducing inflammation in adipose tissue, insulin resistance and risk of chronic disease. Although there is a consensus that exercise training protects against some types of cancer11, 102, it is not yet known whether this is due to alterations in immunological and inflammatory mechanisms. Finally, it should be noted that further research is needed to clearly demonstrate the direct and indirect molecular mechanisms by which physical exercise influences immune function. There can be no doubt that regular exercise is beneficial for health, but a major challenge is to encourage more of the general population to engage in more of it.
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