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Figure 1 | The effect of diet and physical activity on inflammation and disease. A healthy diet and physical activity
maintain the anti-inflammatory phenotype of adipose tissue, which is marked by small adipocyte size and the presence of
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anti-inflammatory immune cells, such as M2‑type macrophages and CD4+ regulatory T (TReg) cells. A positive energy balance
and physical inactivity lead to an accumulation of visceral fat and adipose tissue infiltration by pro-inflammatory
macrophages and T cells. The pro-inflammatory M1 macrophage phenotype predominates and inflamed adipose tissue
releases pro-inflammatory adipokines, such as tumour necrosis factor (TNF), which causes a state of persistent low-grade
systemic inflammation. This may promote the development of insulin resistance, tumour growth, neurodegeneration and
atherosclerosis. Atherosclerosis is exacerbated by the deleterious changes in the blood lipid profile that are associated with
Immunometabolism a lack of physical activity. LDL, low-density lipoprotein; IL‑6, interleukin‑6;TLR, Toll-like receptor.
This term has been recently
introduced to describe the
multilevel interactions between
the metabolic and immune effect and briefly discuss the implications for the use of results in increased production of pro-inflammatory
systems. exercise as a medicine in the prevention and treatment of adipokines, such as TNF, leptin, retinol-binding pro-
chronic disease. We also consider the impact of intensive tein 4, lipocalin 2, IL‑6, IL‑18, CC‑chemokine ligand 2
Adipokines
training on infection risk for endurance athletes. (CCL2; also known as MCP1), CXC-chemokine ligand 5
Factors, including cytokines,
that are secreted from adipose and angiopoietin-like protein 2 (REF. 4). Conversely, the
tissue. Some adipokines Anti-inflammatory effects of exercise amounts of anti-inflammatory cytokines (for example,
promote inflammatory Recent reviews on the anti-inflammatory effects of adiponectin and secreted frizzled-related protein 5) are
responses and metabolic exercise15–17 have focused on three possible mecha- reduced4. This leads to the development of a persistent
dysfunction, whereas others
have anti-inflammatory
nisms: the reduction in visceral fat mass; increased state of low-grade systemic inflammation29.
functions and beneficial effects production and release of anti-inflammatory cytokines Regular exercise can reduce waist circumference and
on metabolic disorders. from contracting skeletal muscle (such molecules are cause considerable reductions in abdominal and visceral
termed myokines15,18); and reduced expression of Toll- fat, even in the absence of any loss of body weight, in
Insulin resistance
like receptors (TLRs) on monocytes and macrophages17 both men and women regardless of age30. Furthermore,
A condition characterized by
the inability of cells in the (with subsequent inhibition of downstream responses, regular exercise results in higher circulating levels of
muscle, liver and adipose such as the production of pro-inflammatory cytokines adiponectin and lower levels of several circulating pro-
tissue to respond appropriately and the expression of MHC and co-stimulatory mol- inflammatory adipokines, including IL‑6, TNF, retinol-
to endogenous insulin, ecules)19. In addition, mouse studies have revealed that binding protein 4 and leptin31–33. It is not known whether
resulting in increased blood
glucose levels.
the anti-inflammatory effects of exercise also rely on the levels of the other adipokines (mentioned above)
other mechanisms, such as the inhibition of monocyte are reduced in the blood following exercise, and further
Triglycerides and macrophage infiltration into adipose tissue20 and the research is needed to address this. So, increased physical
The storage form of fat found in phenotypic switching of macrophages within adipose activity can bring about a reduction in systemic inflam-
adipose tissue.
tissue20. Although these types of analysis are difficult to mation29 via a decrease in pro-inflammatory adipokine
Low-density lipoprotein conduct in humans, analysis of human peripheral blood secretion, which is a direct result of lowering the amount
(LDL). A protein–lipid complex following exercise has revealed a reduction in the circu- of fat stored in abdominal depots.
in the blood plasma that lating numbers of pro-inflammatory monocytes21 and an
facilitates the transport of increase in the circulating numbers of regulatory T cells Release of IL‑6 from contracting muscle. At rest, approx-
triglycerides, cholesterol and
phospholipids. High blood
(TReg cells)22,23. This suggests that such mechanisms may imately 30% of circulating IL‑6 arises from the adipose
levels of LDL are associated also be involved in the anti-inflammatory effects of exer- tissue34, but only about 10% of this can be attributed to
with an increased risk of cise in humans. However, there are some limitations in the adipocytes35 with the remainder coming mostly from
coronary heart disease. the study of the immunological effects of exercise (both adipose tissue-resident macrophages. Other sources of
acute and chronic) in humans; these types of study and circulating IL‑6 include blood leukocytes (predomi-
High-density lipoprotein
(HDL). A protein–lipid complex their limitations are summarized in BOX 2. nantly monocytes), the brain and the liver. During and
in the blood plasma that following exercise of sufficient load, the active skeletal
facilitates the transport of Reduction in visceral fat mass. The accumulation of muscle markedly increases both cellular and circulat-
triglycerides, cholesterol and body fat — particularly in the abdomen, liver and mus- ing levels of IL‑6 (REF. 36). With prolonged exercise
phospholipids. High blood
levels of HDL are associated
cles — is associated with increased all-cause mortality 24 (over 2.5 hours), IL‑6 levels can increase over 100‑fold,
with a decreased risk of and the development of T2D25, CVD26, dementia27 and although more modest increases are reported with exer-
coronary heart disease. several cancers28. The expansion of the adipose tissue cise of a shorter duration37. Increases have also been
Table 1 | A summary of the associations between physical activity and major diseases*
Disease Evidence that physical activity may lower disease risk and/or have therapeutic value in
treating disease
CHD A large body of epidemiological evidence demonstrates that high levels of physical activity and physical
fitness are associated with a lower risk of developing CHD. RCTs show that regular physical activity can
favourably modify CHD risk factors, including (but not limited to) dyslipidaemia, hypertension and obesity.
RCTs also show that physical activity improves survival in CHD patients.
Stroke Evidence suggests that high levels of physical activity and physical fitness reduce the risk of stroke,
although the data are not as compelling as those for CHD. RCTs show that physical activity can lower (but
not necessarily normalize) blood pressure in hypertensive individuals.
Cancer High levels of physical activity are associated with a lower risk of colon and breast cancer. Physical activity
may lower cancer risk by systemic mechanisms (such as reduced body fat and insulin levels, and enhanced
immune function) and site-specific mechanisms (namely, reduced levels of sex steroid hormones for
breast cancer, and decreased bowel transit time for colon cancer). Some observational and RCT evidence
supports a therapeutic role for physical activity in preserving mobility and function in cancer patients.
Regulatory T cells T2D Observational epidemiological evidence consistently demonstrates an association between high levels of
(TReg cells). A specialized physical activity and/or fitness and a reduced risk of developing T2D. RCTs show that lifestyle intervention
subpopulation of T cells that (diet and physical activity) can lower body mass, improve glucose tolerance and reduce the risk of
acts to suppress activation of developing T2D in high-risk patients. In patients with T2D, high levels of physical activity and physical
the immune system and fitness are associated with a reduced risk of CHD and all-cause mortality.
thereby maintains immune
Dementia Observational epidemiological studies indicate that higher levels of physical activity are associated with
system homeostasis and
a lower risk of cognitive decline and dementia in older adults. Some limited evidence is available from
tolerance to self antigens.
RCTs to suggest that physical activity induces modest improvements in cognition in individuals who are at
These cells are involved in
increased risk of Alzheimer’s disease or other forms of dementia.
shutting down immune
responses after they have Other There is some evidence from observational and intervention studies to support a role for physical
successfully tackled invading activity in enhancing physical function and improving quality of life in those suffering from chronic heart
microorganisms, and also in failure, chronic obstructive pulmonary disease, depression, intermittent claudication, osteoarthritis and
regulating immune responses osteoporosis.
that may potentially attack CHD, coronary heart disease; RCT, randomized controlled trial; T2D, type 2 diabetes mellitus. *See REFS 8,9 for further detail.
one’s own tissues
(autoimmunity).
noted using intermittent exercise protocols of relatively and the co-stimulatory molecules CD80 and CD86 on
Leptin short duration38. The increase in IL‑6 during exercise antigen-presenting cells, and it has also been shown to
A regulatory hormone that is
produced by adipocytes. When
is transient, normally returning to resting levels within promote the differentiation of DCs expressing low lev-
released into the circulation, it 1 hour after exercise. The plasma IL‑6 concentration els of MHC class II, CD80 and CD86 (REF. 44). In addi-
influences the hypothalamus to increases exponentially with exercise duration, and a tion, IL‑10 downregulates or completely inhibits the
control appetite, and its major stimulus of its synthesis and release appears to be a expression of several pro-inflammatory cytokines and
production correlates with the
fall in muscle glycogen content39,40. Increases in intracel- other soluble mediators, thereby further compromising
amount of adipose tissue.
lular calcium levels and increased formation of reactive the capacity of effector T cells to sustain inflammatory
Adiponectin oxygen species are also capable of activating transcrip- responses44,45. Thus, IL‑10 is a potent promoter of an
A cytokine released from tion factors that are known to regulate IL‑6 synthesis37. anti-inflammatory state.
adipocytes that has The transient rise in circulating IL‑6 during exer- Circulating levels of IL‑10 are lower in obese subjects,
anti-inflammatory effects and
acts as an insulin sensitizer.
cise appears to be responsible for a subsequent rise in and acute treatment with IL‑10 prevents lipid-induced
circulating levels of the anti-inflammatory cytokines insulin resistance46. Moreover, IL‑10 increases insulin
Cortisol IL‑10 and IL‑1 receptor antagonist (IL‑1RA), and it sensitivity and protects skeletal muscle from obesity-
A steroid hormone secreted also stimulates the release of cortisol from the adrenal associated macrophage infiltration, increases in inflam-
from the adrenal cortex in
glands41. This is demonstrated with the observation matory cytokines and the deleterious effects of these
response to stress that has
anti-inflammatory as well as that intravenous infusion of IL‑6 mimics the acute cytokines on insulin signalling and glucose metabolism46.
catabolic effects. anti-inflammatory effects of a bout of exercise, both The action of IL‑6 and the subsequent cascade
with regard to elevation of plasma IL‑10, IL‑1RA and of anti-inflammatory cytokines is not the only mecha-
Adrenaline cortisol41 and with regard to suppression of endotoxin- nism responsible for the health benefits that are associ-
A catecholamine secreted from
the adrenal medulla in
stimulated increases in TNF levels42. ated with exercise, as elevations of IL‑6 do not occur
response to stress that has IL‑1RA is secreted mainly by monocytes and mac- with short durations of low to moderate intensity exer-
effects on the cardiovascular rophages and inhibits the pro-inflammatory actions of cise37 despite the known health benefits (for example,
system (for example, increased IL‑1β43. IL‑10 is known to be produced primarily by TReg reduced risk of heart disease) associated with only very
heart rate and peripheral
cells but also by T helper 2 (TH2) cells, TH1 cells, TH17 moderate increases in physical activity above that of a
vasoconstriction) and on
metabolism (for example, cells, monocytes, macrophages, dendritic cells (DCs), sedentary lifestyle47,48.
increased glycogen breakdown B cells and CD8+ T cells44. Irrespective of the cellular
and lipolysis). It also has some source, the principal function of IL‑10 appears to be the Increased levels of circulating cortisol and adrenaline.
immunosuppressive effects (for downregulation of adaptive immune responses45 and Secretion of the adrenal hormones cortisol and adrenaline
example, decreased
pro-inflammatory cytokine
minimization of inflammation-induced tissue damage. is increased during exercise owing to activation of the
production by monocytes and In detail, IL‑10 downregulates the expression of MHC hypothalamic–pituitary–adrenal axis and the sympathetic
lymphocytes). molecules, intercellular adhesion molecule 1 (ICAM1) nervous system (SNS). Impulses from the motor centres
inflammation in adipose tissue. Inflamed adipose tis- stimulation with known TLR ligands, such as LPS and
sue appears to be associated with a preferential recruit- zymosan71. Whether this reduction in cell surface expres-
ment of M1‑type macrophages and/or a phenotypic sion of TLRs is due to downregulation of TLR gene
switch of adipose tissue macrophages towards the M1 expression, shedding of TLRs from the cell surface or
phenotype68. Therefore, it is possible that the attenuated re-internalization by the cell remains to be established.
inflammatory state of adipose tissue that is associated The precise physiological stimulus that mediates an
with chronic exercise training occurs by both suppres- exercise-induced decrease in cell surface TLR expres-
sion of macrophage infiltration and acceleration of phe- sion is not known; however, several possible signals have
notypic switching from M1- to M2‑type macrophages. been implicated, including anti-inflammatory cytokines,
Indeed, a recent study in mice fed a high-fat diet to stress hormones and heat shock proteins19.
induce obesity provided some evidence that exercise The evidence discussed above points to a downregu-
training induces this phenotypic switching from M1- lation of TLR expression and subsequent downstream
Noradrenaline to M2‑type macrophages in adipose tissue and inhibits inflammatory signalling cascades with acute exercise.
A catecholamine secreted from M1‑type macrophage infiltration into adipose tissue20. However, as prolonged exercise increases lipolysis and
sympathetic nerve endings
However, studies in humans are still scarce. elevates plasma levels of free fatty acids, which are
that has effects on the
cardiovascular system (for ligands for TLR2 and TLR4 (REF. 74), it might be sur-
example, increased heart rate Downregulation of TLR expression. TLRs are highly mised that exercise could induce inflammatory cascades
and peripheral conserved transmembrane proteins that have an impor- via activation of TLRs. However, there is no direct evi-
vasoconstriction) and on tant role in the detection of microbial pathogens and in dence for this, and LPS-stimulated cytokine production
metabolism (for example,
increased glycogen breakdown
the recognition of endogenous danger signals released by blood monocytes is clearly reduced, not increased,
and lipolysis). It also has some following tissue damage, such as heat shock proteins69. following prolonged exercise42,71,75.
immunosuppressive effects (for Activation of TLR signalling results in increased expres-
example, decreased sion and secretion of pro-inflammatory cytokines and Reduced numbers of pro-inflammatory monocytes
pro-inflammatory cytokine
thus has an important role in mediating systemic inflam- in blood. There are two main populations of mono-
production by monocytes and
lymphocytes). mation70. Evidence is now emerging that TLRs may be cytes: classical (CD14 hiCD16 –) and non-classical
involved in the link between a sedentary lifestyle and (CD14lowCD16+ or CD14hiCD16+). These subsets differ-
M1‑type macrophages inflammation and disease. Exercise training studies entially express cell surface TLR4, with the inflammatory
Macrophages that are and cross-sectional comparisons between physically CD14lowCD16+ monocytes expressing 2.5 times as much
activated in the presence of
TH1-type cytokines, such as
active and inactive subjects have shown that blood cell surface TLR4 as the other populations76. Despite
interferon-γ, and produce, monocytes from physically active individuals have a constituting only 10% of the total monocyte popula-
among other molecules, reduced inflammatory response to endotoxin stimu- tion, inflammatory monocytes contribute significantly
inducible nitric oxide synthase lation in vitro. These cells also have decreased TLR4 to the inflammatory potential of the monocyte pool
and nitric oxide.
expression (at both cell surface protein and mRNA lev- as a whole77. The percentage of circulating inflamma-
M2‑type macrophages els)17,19, which is associated with decreased inflammatory tory monocytes is elevated in patients with rheumatoid
Macrophages that are cytokine production71. arthritis78, CVD79 and T2D80, and it has been suggested
activated in the presence of Following an acute, prolonged bout of strenuous that inflammatory monocytes play a significant role in
TH2-type cytokines, such as exercise, the expression of TLR1, TLR2 and TLR4 on the pathogenesis of several diseases linked to inflamma-
interleukin‑4 (IL‑4) or IL‑13,
and express arginase 1, the
monocytes is decreased for at least several hours19,72,73. tion. Transient increases in the numbers of inflamma-
mannose receptor CD206 and Prolonged exercise also results in a decreased induction tory monocytes have been observed after a single, acute
the IL‑4 receptor α-chain. of co-stimulatory molecules and cytokines following bout of intense exercise81, followed by a rapid return to
Taken together, these findings suggest that each bout decreased release of adipokines) and the induction of an
of exercise induces an anti-inflammatory environment. anti-inflammatory environment with each bout of exer-
Various mechanisms can contribute to this (FIG. 2), and cise. Various mechanisms may contribute to the genera-
it seems likely that their relative importance will vary tion of this anti-inflammatory environment, including:
depending on the frequency, intensity and duration of increased release of cortisol and adrenaline from the
the exercise performed. For low-intensity exercise, such adrenal glands; increased production and release of
as brisk walking, it is likely that the control of body fat is IL‑6 and other myokines from working skeletal muscle;
the most important mechanism, but for short periods of reduced expression of TLRs on monocytes and macro
high-intensity exercise and prolonged moderate-intensity phages (with subsequent inhibition of downstream
exercise the other anti-inflammatory effects may have an pro-inflammatory cytokine production); inhibition
increasingly important role. of adipose tissue infiltration by monocytes and mac-
rophages; phenotypic switching of macrophages within
The elite athlete paradox adipose tissue; a reduction in the circulating numbers of
Although regular moderate-intensity exercise is associ- pro-inflammatory monocytes; and an increase in the cir-
ated with a reduced incidence of upper respiratory tract culating numbers of TReg cells. These anti-inflammatory
infection compared with a completely sedentary state93,94, effects of exercise are also likely to be responsible for
the long hours of hard training that elite athletes under- the partial immunosuppression that makes elite athletes
take appears to make them more susceptible to upper more susceptible to common infections.
respiratory tract infections 11,95–98. This is probably At present, we do not know the relative importance of
attributable to the anti-inflammatory effects of exercise these different anti-inflammatory mechanisms, although
inducing a degree of immunosuppression11,98, although it seems likely that this will depend on the mode, fre-
other factors — such as psychological stress, disturbed quency, intensity and duration of the exercise performed.
sleep and negative energy balance — may contribute to Intuitively, we might expect IL‑6 to assume greater rela-
immunosuppression in elite athletes98. An increased risk tive importance when the exercise is prolonged and
of minor infections may be the (small) price to be paid glycogen-depleting, whereas catecholamine-mediated
for the long-term health benefits of regular exercise at effects are likely to assume greater importance with
high dosage. shorter duration, high-intensity exercise. High training
A recent murine study indicated that intensive exer- loads may be needed to increase circulating numbers of
cise training results in an increased anti-inflammatory TReg cells and maximize the anti-inflammatory effects, but
cytokine (IL‑10) response to antigen exposure23. Moreover, possibly at the cost of a small increase in infection risk.
a study on human endurance athletes revealed that whole Further research should establish the mode, intensity
blood cultures from athletes who were prone to illness and duration of exercise required to optimize the anti-
during a 4‑month period of winter training produced inflammatory effects, and it still remains to be estab-
four times as much IL‑10 following antigen stimulation lished whether exercise is always useful as a therapy for
as blood cultures from athletes who remained illness-free the treatment of patients with inflammation-associated
during the same period99. There is now extensive evidence disorders. Furthermore, we still need to determine the
from both murine and human studies that IL‑10 produc- independent contribution of an exercise-induced reduc-
tion usually imposes some limits on the effectiveness of tion in visceral fat (versus other exercise-induced anti-
pathogen-specific immune responses, especially innate inflammatory mechanisms) in reducing inflammation
immunity and adaptive TH1 cell responses100,101. These in adipose tissue, insulin resistance and risk of chronic
studies suggest that very high training loads induce an disease. Although there is a consensus that exercise train-
anti-inflammatory state that is sufficient to increase the ing protects against some types of cancer11,102, it is not
risk of minor infections. yet known whether this is due to alterations in immuno-
logical and inflammatory mechanisms. Finally, it should
Conclusions and remaining questions be noted that further research is needed to clearly dem-
Regular exercise reduces the risk of chronic metabolic and onstrate the direct and indirect molecular mechanisms
cardiorespiratory diseases (TABLE 1), in part because exer- by which physical exercise influences immune function.
cise exerts anti-inflammatory effects. The anti-inflam- There can be no doubt that regular exercise is beneficial
matory effects of regular exercise may be mediated via for health, but a major challenge is to encourage more of
both a reduction in visceral fat mass (with a subsequent the general population to engage in more of it.
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