Aerobic but not Resistance Exercise Can Induce Inflammatory Pathways via Toll-Like 2 and 4: a Systematic Review
Cavalcante et al. Sports Medicine - Open
Aerobic but not Resistance Exercise Can Induce Inflammatory Pathways via Toll-Like 2 and 4: a Systematic Review
Paula Andréa Malveira Cavalcante 0 1 2 4 5 8
Marcos Fernandes Gregnani 0 2 3 8
Jessica Salles Henrique 6 7
Fábio Henrique Ornellas 0 1 2 4 8
Ronaldo Carvalho Araújo 0 1 2 3 4 8
0 Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
1 Medicine (Nephrology) Program, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
2 Laboratory of Exercise Genetics and Metabolism, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
3 Molecular Biology Program, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
4 Medicine (Nephrology) Program, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
5 Rua Pedro de Toledo , 669/9and., 04039-032, São Paulo, SP , Brazil
6 Exercise Neurophysiology Laboratory, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
7 Neurology/Neuroscience Program, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
8 Department of Biophysics, Federal University of São Paulo (UNIFESP) , São Paulo, SP , Brazil
Background: Only a few studies have addressed the relationship between toll-like receptors 2 and 4 (TLR2 and TLR4) and the production of local and systemic cytokines in response to physical exercise, and they have produced conflicting results. We aimed to determine whether acute and chronic exercise outcomes are associated with changes in TLR2 and TLR4 expression and signaling and if so, the mechanisms that connect them. Methods: PubMed database were consulted. This systematic review selected 39 articles, 26 involving humans and 13 based on rodents. Results: In acute resistance exercise studies, 75% reported a decrease in TLR4 or TLR2 expression and 25% did not find differences. For chronic resistance exercise studies, 67% reported a reduction of expression and 33% did not find differences. Studies of both types reported reductions in pro-inflammatory cytokines. In acute aerobic exercise studies, 40% revealed a decline in the expression of the receptors, 7% reported no significant difference, 40% showed an increase, and 13% did not evaluate their expression. Fifty-eight percent of studies of chronic aerobic exercise revealed a reduction in expression, 17% did not find a difference, and 25% reported increases; they also suggested that the expression of the receptors might be correlated with that of inflammatory cytokines. In studies on combined exercise, 50% reported a decline in receptors expression and 50% did not find a difference. Conclusions: The majority of the articles (54%) link different types of exercise to a decline in TLR4 and TLR2 expression. However, aerobic exercise may induce inflammations through its influence on these receptor pathways. Higher levels of inflammation were seen in acute sessions (40%) than regular sessions (25%).
TLR2; TLR4; Toll-like; Exercise; Training; Aerobic; Resistance; Inflammation
It is known that regular exercise acts as an anti
inflammatory agent by down-regulating TLR4 in
immune cells. Paradoxically, acute, extended, or intense
exercise can be harmful to the immune system.
The molecular mechanisms by which various types
of physical exercise modulate the TLR2 and TLR4
pathways are still not fully understood.
Physical exercise reduced the expression of TLR2 and TLR4. However, aerobic exercise is potentially inflammatory when compared with resistance exercise.
The connections between lifestyle factors and health
have been the subject of intense research, partly
motivated by alarming changes in the health landscape of
industrialized societies. One clear trend is that moderate
exercise benefits health in many ways, while extremes of
too little or excessive exercise have been linked to
chronic diseases. Many of these have an immune
component—individuals with very sedentary lifestyles often
fall prey to low-grade chronic inflammations [
the long term, this condition can lead to type 2 diabetes,
cardiovascular diseases, particular types of cancer,
chronic respiratory diseases, and other serious health
problems. Physicians have called this constellation a
worldwide epidemic . The immune system can also be
disrupted by excessive exercise. While progress has been
made, there remain many gaps in our understanding of
the mechanisms that connect the types and amounts of
a person’s activity to immune responses and disease.
The prevalence of inflammations suggests a logical
point of departure for such studies. Inflammation
involves complex interactions at the molecular and cellular
levels that can arise in any vascular tissue as a result of
traumatic, infectious, post-ischemic, toxic, or
autoimmune injuries [
]. Toll-like receptors play a role in
many of these conditions; they are known to make
significant contributions to obesity [
], type 2 diabetes
, non-alcoholic steatosis [
], cardiovascular disease
], cerebral ischemia [
], Alzheimer’s disease
], rheumatoid arthritis [
], and other diseases. This
review examined recent work that suggests they also
help modulate the effects of different levels of physical
activity on states of health and disease.
TLRs are type I transmembrane proteins involved in
both innate and adaptive immune system responses [
]. These receptors mediate the recognition of
pathogen-associated molecular patterns (PAMPs) or
damage-associated molecular patterns
(DAMPs)—specific molecules released by damaged or necrotic cells [
]. The immune activities of TLRs are generally
modulated through signaling via the NF-kB pathway.
Responses begin with the stimulation of the receptor by an
external signal. This alters the cytoplasmic regions of
TLRs, which contain Toll/interleukin-1 (IL-1) receptor
(TIR) domains. Stimulation causes these domains to
recruit adaptor proteins in a process that ultimately
activates the nuclear transcription factor NF-kB [
releases NF-kB for transport to the cell nucleus, where it
triggers the transcription of cytokines including IL-1β,
IL-6, and IL-8 interleukins; TNF-α [
]; and other
] that play key roles in the immune system
responses. Alongside cytokines, NF-kB induces the
expression of growth factors and other molecules involved
in stress response, cell proliferation, and cell cycle
TLRs are expressed in the immune cells including
macrophages, dendritic cells (DCs), B cells, and specific
types of T cells. They are also present in non-immune
cells such as fibroblasts and epithelial cells [
] and in
the tissues of the ovary, prostate, placenta, testicles,
lungs, liver, and skeletal muscle [
The toll-like receptors TLR2 and TLR4 have received
particular attention due to their ability to identify
molecular patterns exhibited by several invasive
]. They also seem to play an important role in
the anti-inflammatory effects observed in physically
active individuals [
]. Regular exercise has been
determined to have anti-inflammatory effects [
downregulating TLR4 in the immune cells. A bit
paradoxically, at the other end of the activity spectrum,
acute, extended, or intense exercise can have a negative
impact on the immune system [
]. But the
molecular mechanisms by which exercise modulates the TLR2
and TLR4 pathways are still not fully understood.
One plausible link comes from the demonstration that
TLR2 and TLR4 are activated by the extracellular
nonesterified fatty acids (NEFAs). Concentrations of
extracellular NEFAs undergo transient increases during
aerobic exercise (AE). If levels are chronically elevated,
however, TLRs may induce the production of
proinflammatory cytokines in macrophages, adipocytes,
liver, and skeletal muscle cells. This suggests that the
receptors may participate in the development of insulin
]. Yet, they also have protective effects
against insulin resistance, which may be explained by
the down-regulation of TLR expression that occurs
during physical exercise [
Here, this review investigated the existing literature on
the inflammatory and anti-inflammatory effects of
different types of physical exercise with a focus on
systematically collecting connections to TLR2 and TLR4
modulation and signaling. To accomplish this, the
results were divided into single sessions of acute exercise
and chronic exercise, based on periodicity. Additionally,
this review identified key biomarkers and analyzed the
combined TLR2 and TLR4 responses to markers
involved in the process of inflammation process, including
anti- and pro-inflammatory cytokines, adaptor proteins,
and the transcription factor NF-kB.
Inflammatory Effects of Physical Exercise
Analyzing the modulation of inflammation patterns
permits insights into specific underlying physiological
mechanisms. As a controllable model of stress, physical
exercise is a good tool to analyze inflammatory
Physical exercise permits the control of variables
related to activity such as volume, intensity, frequency,
and duration. These factors have led to its adoption as a
good strategy to study alterations that occur due to
inflammations caused by stress and their implications for
]. Local and systemic cytokine production
in response to physical exercise resembles the cytokine
response to infections, trauma, and sepsis [
44, 45, 48
There is evidence that very strenuous physical exercise can
cause substantial tissue damage and initiate an
inflammatory reaction and excessive immunosuppression, in a way
that highly resembles features observed in clinical sepsis
]. However, trauma, infection, and septic complications
can produce an uncontrollable inflammatory response with
long-term detrimental or fatal consequences. In physical
exercise, although the inflammatory cascade has obvious
similarities, the response appears to be limited [
Usually, the process of inflammation has an overall
positive effect on the organism. Short-term, acute
inflammation allows the body to survive progressive tissue
destruction by promoting healing [
]. On the other
hand, if destruction and repair are not properly
coordinated, inflammation may lead to persistent tissue damage.
The mechanisms by which acute inflammation starts and
develops are well understood, but little is known about
the causes of chronic inflammation and its association
with molecular and cellular pathways .
A comparison can also be made between chronic
inflammation and strenuous physical exercise in which
proinflammatory pathways seem to be activated [
38, 41, 52
In response to heavy exercise, inflammation stimulates
tissue monocyte production, and platelet hyperactivity
promotes fibrinogen biosynthesis and induces the formation
of the microparticle and the accumulation of erythrocytes
to trigger a prothrombotic state. In fact, vigorous aerobic
exercise may be atherogenic and atherothrombotic due to
the overproduction of mitochondrial-free radicals in the
skeletal and myocardial muscle. On the other hand, both
moderate AE and low-load resistance exercise (RE) may
reduce inflammation and improve fibrinolysis. [
An elegant study [
] found associations between all
causes of mortality and doses of jogging. Light and
moderate joggers had a lower mortality than sedentary
nonjoggers, while there was no significant statistical
difference between mortality in strenuous joggers and the
sedentary group. In this analysis, high running loads in
sports such as marathons, ultramarathons, triathlons,
and long high-intensity bike rides can cause negative
effects such as acute inflammations; in the long term,
these activities may lead to chronic inflammation,
irregular fibrosis formation, alterations in the size of the
cardiac chambers, and atrial fibrillation [
long-distance runners may have increased levels of
atherosclerosis and coronary disease due to constant
training throughout the year [
]. In atherosclerosis,
the endothelial permeability is increased by the
oxidative damage that promotes the entry of lipoproteins
in the subendothelial space, resulting in inflammation
]. When the lipoproteins are oxidative, they
interact with TLR4 in particular and promote
cardiovascular disease [
According to the American College of Sports Medicine
(ACSM) and the American Heart Association [
minimum recommendation for physical exercise for
adults and seniors aiming to avoid chronic disease is
30 min of moderate aerobic activity per day, five times a
week; 20 min per day of intense activity, three times a
week; or a combination of moderate and vigorous
activity. These guidelines also suggest that high loads of AE
may be necessary for some groups to prevent a
transition to an estimation that they are overweight or a
diagnosis of obesity. However, they also recommend limiting
vigorous physical training to 60 min a day, for a weekly
total of no more than 5 h, including 1 to 2 days without
high-intensity exercise per week [
]. Strenuous AE
has been shown to induce an excess of reactive oxygen
species (ROS) ; can modulate TLR4 signal
transduction at many levels [
]; stimulate pro-inflammatory
transcription factors such as NF-kB, AP-1, and Nrf2 [
]; and promote inflammation .
NADPH oxidase 4 (NOX4), involved in redox
signaling in vascular cells, has direct interactions with TLR4 in
both for the generation of endogenous and exogenous
ROS-mediated by LPS and the activation of NF-kB [
In addition, high levels of ROS in the muscles can
provoke a hyperactivation of the innate immune system in
cells such as macrophages and neutrophils [
], and it
leads to the production of several peroxides and
aldehydes that are potentially toxic to the cells [
affecting T cell polarization and contributing to
proinflammatory cytokine secretion [
]. It is already
known that ROS production and neutrophil counts
change in athletes involved in activities such as running,
jumping, throwing, combined events (triathlon,
heptathlon, and decathlon), swimming, cycling, and soccer, but
only high-intensity exercise induces oxidative damage in
]. In contrast, moderate-intensity AE
stimulates the combat of excessive ROS by maintaining
redox balance in the muscle [
]. A study [
] of soccer
players showed a significant correlation between
leukocyte ROS production and creatine kinase (CK)
values, considered a qualitative marker for microtrauma
In fact, the physiological effects of strenuous AE, for
example, participation in triathlons, include a large
increase in CK, C-reactive protein (CRP), cortisol, and
aldosterone and a decrease in testosterone levels [
Moreover, after strenuous exercise, increased levels of
LPS may trigger an increase in the production of
proinflammatory cytokines [
]. Long periods of AE
 or short acute sessions of strenuous physical
] can disturb homeostasis and enhance
inflammation. Consistent with this, Rodrigues-Miguelez et al.
] found an increase in TLR4 and pro-inflammatory
cytokines such as TNF-α and IL-1β in acute AE sessions;
however, the effects were reversed with regular training
in reasonable doses.
TNF-α represents a group of peptides that are released
into the bloodstream in response to the endotoxin
stimulation during infectious processes. TNF-α has a
catabolic effect [
] and plays a role in the loss of
muscle mass that usually appears in chronic diseases
such as rheumatoid arthritis and cancer [
genesis in low-grade systemic inflammation is thought
to occur mainly in the adipose tissue [
Furthermore, systemic inflammation and high concentrations of
pro-inflammatory cytokines act on the
hypothalamicpituitary-adrenal axis and can increase serum
concentrations of cortisol [
]. Physical exercise and nutrition
modulate the cortisol response. Variables such as
intensity, lactate accumulation, total volume, and resting
period determine the level of cortisol released to
stimulate glycogenolysis and gluconeogenesis [
Moderate- to high-intensity exercise can cause increases in
circulating levels of cortisol. On the other hand,
lowintensity exercise (40% VO2max) reduces circulating
levels of cortisol [
]. In the study by Lira et al. [
TLR-4 and NF-kBp65 were increased in animals from
both groups (overtraining and resting after overtraining).
Additionally, a decrease in the performance and an
increase in the production of corticosterone and endotoxin
were observed in overtraining groups compared to both
control and trained groups, indicating that chronically
high levels of plasma cortisol can increase inflammation
in the epididymal adipose tissue.
Thereby, an excess of physical (blood cortisol levels)
and oxidative stress (intracellular ROS accumulation)
can generate temporary immune dysfunction [
contrast, physical exercise at moderate intensities
regulates the immune system and reduces oxidative
]. Figure 1 presents a simplified comparison
of some mechanisms that can be activated by
strenuous physical exercise and by regular exercise
performed at moderate intensity.
Anti-inflammatory Effects of Physical Exercise
It is well known that regular physical exercise has
antiinflammatory effects [
8, 29–31, 88–93
regular physical exercise, as well as a physically active
lifestyle, may be useful as a treatment for a range of chronic
diseases and conditions characterized by low-grade
systemic inflammation [
However, the link between physical exercise and
TLRs is still a matter of debate. Although the
proinflammatory effects of TLR2 and TLR4 signaling
have been well studied, anti-inflammatory responses
due to the activation of these receptors are still not
fully understood [
]. For this reason, this article will
briefly address a number of molecules that act
directly during the processes of adaptation to physical
exercise—including hormones, myokines, and
chemical molecules such as ROS.
The skeletal muscle can function as an endocrine
organ due to its production of growth hormones and
cytokines known as myokines, which are induced by an
exercise stimulus [
]. One of the best-known
exerciseinduced adaptations [
] is an increase in circulating
levels of insulin-like growth factor 1 (IGF-1). Elevated
levels of circulating IGF-1 have been observed after
exercise, probably in response to hepatic secretion
stimulated by growth hormone (GH) [
The first evidence that IGF-1 is a potent modulator of
TLR4 (protein expression) in the skeletal muscles was
provided by Lee [
]. The author demonstrated that
IGF-1 stimulation had anti-inflammatory effects on the
skeletal muscle and suppressed TLR4 signaling.
Treatment with IGF-1 attenuated the amounts of endogenous
IL-6 and TNF-α, indicating that IGF-1 had an
antiinflammatory effect on the skeletal muscle cells by
reducing the expression of pro-inflammatory cytokines under
baseline conditions through a down-regulation of the
expression of TLR4. This led to a hypothesis that cells with
low levels of TLR4 are less responsive to ligands that
stimulate endogenous inflammation, such as the heat
shock protein, and thus contribute to a lower basal
response of pro-inflammatory cytokines [
]. In addition
to the anti-inflammatory effects of IGF-1, regular AE
promotes the remodeling of mitochondrial networks
with significant improvements in both the quality and
quantity of the mitochondria [
]. This results in
positive changes in the respiratory capacity and oxygen
extraction of trained subjects [
Likewise, there is an increase in angiogenesis, the
formation of new capillaries from pre-existing ones. High levels
of VEGF—resulting from endurance training—offer
favorable conditions for an increase in the density of the
muscle capillaries [
]. Furthermore, a moderate level of
AE reduces pro-atherogenic cytokines such as TNF-α and
IFN-γ and simultaneously increases atheroprotective
cytokines such as IL-4, IL-10, and TGF-β [
The anti-inflammatory effects of regular exercise
might be mediated by a reduction of visceral fat mass
followed by a decline in the release of adipocytokines, as
well by the anti-inflammatory environment induced by
]. This environment consists of three
variables: cortisol and adrenaline release from suprarenal
glands, an increase in the production and release of IL-6
and other myokines from skeletal muscle, and a decrease
in amounts of TLR (cell surface protein and mRNA
expression) - in monocytes and macrophages, and as a
consequence, the inhibition of the release of
proinflammatory cytokines [
In fact, there is evidence that exercise is responsible
for reducing the expression of these receptors at both
mRNA expression and protein levels [
2, 29, 30, 32, 93
In diet-induced obesity rats (DIO), both acute aerobic
exercise (AAE) and chronic aerobic exercise (CAE) led
to a significant suppression of the TLR4 signaling
pathway in liver, muscle, and adipose tissue, reduced LPS in
serum, and improved insulin signaling [
]. However, the
anti-inflammatory responses induced by TLR4 activation
have not been characterized as clearly. In contrast to
TLR4 pro-inflammatory signaling at the cell surface,
TLR4 signaling from endosomal compartments induces
the secretion of the anti-inflammatory cytokine IL-10
During physical exercise, a transient increase in IL-6
in circulation appears to be responsible for a further
increase in the levels of circulating anti-inflammatory
cytokines such as IL-10 and IL-1ra [
]; this also
stimulates the release of cortisol from the adrenal glands
]. Increases in IL-6 levels during exercise are
transient and return to resting levels usually within 1 h after
]. This phenomenon may occur because
IL6 production is modulated by the glycogen content in
], which function as an energy sensor [
The anti-inflammatory effects of TLR2 and TLR4
during exercise are mediated by the PI3K/AKT/mTOR
pathway after an activation of adaptor proteins, leading
to the production of IL-10 (Fig. 1) [
antiinflammatory cytokine produced by Th1 cells,
monocytes, and macrophages that is present in higher
concentrations after physical exercise and acts as a potent
inhibitor of pro-inflammatory cytokines [
IL-10/IL-10R signaling is mediated by the activation of
the JAK/STAT pathway through the phosphorylation of
the Tyk2/JAK1 tyrosine, which results in the activation
of STAT3 [
]. This mechanism is independent of the
toll-like pathway. An analysis of the IL-10/TNF-α ratio
is often used as an indicator of inflammatory conditions
]. This is evidence that IL-10 acts as a natural
antagonist of TNF-α and is able to inhibit NF-κβ
], as shown in Fig. 1.
This review consulted the PubMed database in a search
involving seven keywords: “exercise,” “training,”
“physical activity,” “TLR,” “TLR2,” “TLR4,” and “toll-like,” To
cross-reference the words, 12 groups were created to
link terms associated with exercise (“exercise,” “training,”
“physical activity”) to toll-like terms (“TLR,” “TLR2,”
“TLR4,” and “toll-like”), building groups formed from
two individual keywords linked by the Boolean operator
“AND.” This produced groups organized as follows:
group 1: “exercise” and “TLR”; group 2: “exercise” and
“TLR2”; group 3: “exercise” and “TLR4”; group 4:
“exercise” and “toll-like”; group 5: “training” and “TLR”; group
6: “training” and “TLR2”; group 7: “training” and
“TLR4”; group 8: “training” and “toll-like”; group 9:
“physical activity” and “TLR”; group 10: “physical
activity” and “TLR2”; group 11: “physical activity” and
“TLR4”; and group 12: “physical activity” and “toll-like.”
Only studies carried out directly in animal models
(human, rat, and mouse) were included. For scientific
substantiation, 119 scientific articles were also consulted in
addition to the 39 studies which met the criteria of
eligibility for this review.
Criteria which excluded articles from this review,
described in Table 1, fell into categories as follows:
nonEnglish articles; literature reviews; articles that did not
cover Toll-like receptors (TLRs); articles studying TLRs
“Exercise” and “TLR”
“Exercise” and “TLR2”
“Exercise” and “TLR4”
“Exercise” and “Toll-like”
“Training” and “TLR”
“Training” and “TLR2”
“Training” and “TLR4”
“Training” and “Toll-like”
“Physical activity” and “TLR”
“Physical activity” and “TLR2”
“Physical activity” and “TLR4”
“Physical activity” and “Toll-like”
other than TLR2 and TLR4; articles without exercise
protocols; experimental articles that did not use humans, mice,
or rats; and finally, articles that involved diet,
supplementation, or drugs. To do so, codes to link the eligibility criteria
of all of the items found in the search were created.
Initially, 1385 articles were found. After an update, the
search ended up with 1548 articles from the PubMed
database. The updated search was carried out in October
2015. The search group distribution can be seen in
Table 2. Figure 2 shows a flowchart of the article
selection process, as well as how the articles were linked to
the search theme. The total number of articles found
and the distribution of the excluded articles are also
Results and Discussion
To investigate the roles of TLR2 and TLR4 behavior in
the inflammatory and anti-inflammatory effects of
exercise, the results were distributed according to the type of
exercise (resistance, aerobic, and combined) and
frequency of training (acute or chronic), taking the
exclusion criteria into account.
Considering the total of 39 studies that met the
eligibility requirements for this review, 28 articles were based
on the samples from a disease-free setting and 11
samples related to a disease. Three articles studied the
effects of exercise and TLR2 and TLR4 on obesity [
], one on pre-diabetes [
], one on low back pain
], two on cerebral ischemia [
], one on
pulmonary inflammation , one on Alzheimer’s disease [
one on chronic fatigue syndrome [
], and one on
multiple sclerosis and fibromyalgia [
As shown in Table 3, 21 of the 39 eligible articles
(54%) showed a reduction in TLR4 and/or TLR2 at the
levels of both cell surface protein and mRNA expression,
Number of articles
7 (18%) did not show statistically significant differences,
2 articles (5%) did not test TLR4 and/or TLR2
expression but were included in this review for the
evaluation of downstream targets of the receptor
pathways, and 9 articles (23%) reported an increase in
TLR2 and/or TLR4 (gene expression or protein levels)
after AE sessions.
The results were also analyzed by subgroups and
divided according to the type and frequency of training
(Table 3 and Fig. 3). For chronic resistance exercise
(CRE), four articles (67%) reported a reduction of TLR4
and/or TLR2 expression and two (33%) did not show
any significant change. For acute resistance exercise
(ARE), three articles (75%) revealed a decrease in the
expression of these receptors and one study (25%) failed to
find a significant difference. For CAE, seven articles
(58%) reported a reduction in TLR4 and/or TLR2
expression, two studies (17%) did not find a significant
difference, and three articles (25%) found an increase in the
expression of TLR4 and/or TLR2. For AAE, six
experiments (40%) showed a decrease, one (7%) did not show
any difference, six (40%) reported an increase, and two
articles (13%) tested neither TLR2 nor TLR4 expression.
Regarding combined exercise (CE), one study (50%)
reported a reduction in the expression of the receptors
and one study (50%) revealed no significant difference.
Resistance Exercise and Inflammation
Six articles that studied TLR4 and/or TLR2 behavior
with CRE were identified (Table 4). Two studies found a
reduction of TLR4 and TLR2 in terms of protein
], two revealed a decrease in mRNA
], and two did not find a statistically
significant difference [
]. Three articles [
] showed reductions in the protein and gene
expression of TLR4 after an ARE session, and one article 
did not show a significant difference in TLR2 (protein
levels), as shown in Table 5. This systematic review
showed that resistance exercise (RE), whether acute or
chronic, could act as a regulator of inflammation. In this
subset of the literature, we observed no increases in the
expression of TLR4 and/or TLR2 or pro-inflammatory
cytokines after exercise.
Some studies [
30, 124, 125
] corroborate the results of
this review and suggest that CRE may have
antiinflammatory effects. In contrast, ARE may stimulate
changes in metabolic demand and promote inflammatory
responses, whose occurrences is fundamentally determined
by the exercise protocol [
]. In this analysis, ARE
transiently increases circulating levels of CK and
proinflammatory cytokines, e.g., TNF  and IL1β [
Some studies that were not eligible for this review [
have shown that ARE induced microdamage in the skeletal
muscle, along with an increase in inflammation markers
such as IL-6, IL-8, monocyte chemotactic protein-1
(MCP1), CK, and CRP when performed at high levels of stress.
The ten eligible studies of CRE and ARE [
8, 29, 88, 92,
], tested different frequencies, intensities,
and durations of exercise, none of these methods,
however, produced changes in levels of TLR2 and/or TLR4.
In these studies, intensities ranged from 60 to 80% of 1
RM with a gradual increase , or 6–14 RM [
one study [
], the training volume followed a criterion
of progression. Another study [
] used 80, 90, and
95% of maximal volitional strength capacity (MVSC),
with low training volume as the criterion.
Regarding the inflammation markers that were
subjected to the analysis here, neither acute nor chronic RE
increased levels of pro-inflammatory cytokines such as
TNF-α or IL-6. Eight studies tested TNF-α, and the
8, 88, 92, 116, 120, 122
] found a significant
decline of this cytokine. Two studies [
] found no
difference in this marker. Four studies analyzed levels of
IL-6 after RE. Two studies [
] found a drop in
levels, but no significant difference appeared in the
studies by Zanchi et al.  and McFarlin et al. [
The results showed that the RE protocols for both
chronic and acute training adopted by the authors did
not generate a pro-inflammatory response. Instead, three
studies analyzed by this review [
92, 119, 120
an inverse relationship between the TLR2 and TLR4
receptors and IL-10. In the five studies that investigated
IL-10 with RE, four [
8, 92, 119, 120
] found an increase
in this marker and one study found no significant
difference . It is known that IL-10 levels are higher after
chronic exercise, and this anti-inflammatory cytokine
acts as a natural TNF-α antagonist [
Aerobic Exercise and Inflammation
A total of 12 articles verified that TLR4 and TLR2
undergo changes in response to CAE (Table 6). Four
studies verified a significant decrease in TLR4 and/or
13, 15, 76, 115
] in terms of protein levels, two
] showed reductions in mRNA
expression, and one indicated decreases at both the gene and
protein level [
]. Two studies [
] revealed an
increase in TLR4 and/or TLR2 (gene and protein), one
study reported increased mRNA expression , and
two studies [
] did not find any significant
difference in TLR4 expression.
In 15 studies, a relationship between AAE and TLR2
and/or TLR4 was identified (Table 7). Three studies
] found a significant reduction of TLR4 and/or
TLR2 (protein levels), and two revealed a decrease in
mRNA expression [
]. Four studies [
35, 39, 40,
] found an increase in the protein levels of these
receptors, and two studies [
] increased mRNA
expression. One study did not find a significant difference
, and one study reported a significant decline in
TLR4 (mRNA expression) in multiple sclerosis but
found no difference in cases of fibromyalgia [
] did not analyze TLR2 or TLR4
As demonstrated by the results from the analysis of
TLR2 and TLR4 behavior, this review showed that in
23% of all of the articles that were analyzed, AE was
associated with increases in inflammation. These results
differ from previous studies that tested the expression of
these receptors in RE. Ten months of CAE was more
effective than strength and flexibility exercises in reducing
inflammatory markers such as CRP, IL-6, and IL-18 in
the elderly [
Most studies found that CAE reduced the levels of
TLR2 and/or TLR4 [
13–15, 76, 115, 117, 130
the major immunological benefits came with exercise
performed at a moderate intensity [
13–15, 76, 117, 130,
]. On the other hand, Zheng et al. [
] observed an
increase in TLR2 (gene expression) and inflammatory
cytokines such as TNF-α and IL-6 in the regular moderate
intensity exercise group (badminton), with or without
stimulation from microbial antigens. However, cytokine
levels were suppressed after non-microbial antigen
stimulation. The authors attributed this result to possible
improvements in the body’s resistance to invasion by
pathogens in response to regular exercise, indicating that
an increase of these receptors does not necessarily indicate
a negative impact on health, though further research is
still needed to address this possibility.
The chronic low-grade inflammatory profile (CLIP) is
a common feature of the normal aging process, and it is
also involved in the pathogenesis of several age-related
]. CLIP has already been recognized as a
factor that plays a causative role in the development of
sarcopenia. TNF-α and IL-6 are the most commonly
reported inflammatory parameters in these studies [
Additionally, human aging is associated with metabolic
endotoxemia and high levels of signaling of the
RST4NFkB-MAPK pathway in the muscle. These factors may
play a role in the types of insulin resistance mediated by
aging and muscle loss [
]. In this analysis, Ghosh et al.
] observed an increase in TLR4 (mRNA and protein
levels) in older people but not in younger participants.
The study examined people engaged in a progressive
regime of the intensity and volume of training,
ranging from 65 to 80% of VO2max, and an increase in
the duration and number of sessions. Their results
provide evidence that higher LPS flow in the elderly
can play a critical role in age-related sarcopenia and
Studies that did not fit our criteria [
54, 58, 144, 59,
] suggested that CAE performed under conditions of
↑MyD-88, ↑TRAF6, ↑NF-kBp65
↑HIF-1α, ↑VEGF, ↑eNOS, ↑MPO.
↑TNF-α, ↑NFkB, ↑p65, ↑ROS,
↑NEFA, ↑p38MAPK, ↑JNK.
Hsp72-induced stimulation of
neutrophil chemotaxis disappeared
when TLR2 was blocked.
↑IRAK3, ↑creatin kinase 3 h after,
↑plasma myoglobin 3 h after,
↑neutrophil 3 h after
TLR4 returned to basal levels within
4 h after exercise, ↔TLR2.
↑Pain ↑mental fatigue.
↑α2-A, ↑RNAm of β-2 receptor in
leucocytes, ↑COMT RNAm
high stress leads to inflammation in participants of all
ages. They observed that long-distance runners might
have increased levels of atherosclerosis and coronary
heart diseases due to a training regime that went
uninterrupted over many years [
endotoxemia was found in 68% of athletes after a
longdistance triathlon, and LPS levels were associated with
higher levels of CRP [
]. A recent study showed that
24 h of continuous ultramarathon activity resulted in a
higher level of LPS and increased levels of circulating
pro-inflammatory cytokines [
]. In fact, prolonged
intense physical exercise leads to elevated concentrations
of counter-regulatory hormones in plasma such as
cortisol and catecholamines related to low immunity [
In addition, high levels of muscle oxidative stress lead to
an excessive production of ROS and inflammation [
In contrast, regular moderate physical exercise can
compensate for oxidative stress [
Short acute sessions of physical exercise may
disturb homeostasis and increase inflammation [
verified by some of the articles reviewed here [
39, 40, 42
]. With the exception of the study by Light
et al. [
], which tested an AAE protocol at moderate
intensity and in samples obtained from individuals
with disease, studies based on different strenuous
exercise protocols consistently led to increases in TLR4,
TLR2, and pro-inflammatory cytokines [
35, 37, 39, 40,
]. Rodrigues-Migueles et al. [
] found an increase
in TLR4 (protein) and pro-inflammatory cytokines in
AAE sessions. However, all of these effects were
extinguished by CAE through a weekly exercise
protocol of increasing intensity and duration.
In studies which reported increases in TLR2,
TLR4, and pro-inflammatory cytokines after acute
sessions, IL-10 was tested in only three experiments,
all of which revealed a significant increase in the
expression of this cytokine [
36, 37, 118
]. This was
probably caused by a transient increase in IL-6
which then led to a subsequent increase in levels of
]. However, other studies [
indicated that AAE had beneficial effects, as
observed through a decline in terms of protein levels
of TLR2 and/or TLR4 and at the mRNA expression
]. Radom-Aizik et al. [
] verified that
AAE not only prevents the normal effects of aging
in terms of atherosclerosis but also reduces its
symptoms in a manner that promotes cardiovascular
health despite the global stress response that is
generally evoked by this activity.
One exception is a study by Liao et al. [
showed a reduction in TLR4 (gene expression), but also
showed an increase in inflammatory responses as
exhibited by high levels of TNF-α, NF-kB, and LPS. The
reason for the down-regulation of TLR4 is not clear, but
the authors believe that this may be related to high levels
of ROS. Here, from our review of the literature, we
suggest that increases in circulating LPS and an excessive
generation of ROS are the main actors in the acute
inflammatory process generated by excessive AE. However,
more studies are needed to complete the mechanistic
picture that links these effects and other aspects of
inflammatory responses in AE.
Combined Exercise and Inflammation
Only two studies [
] relating TLR2 and/or TLR4
to CE (combining aerobic and resistance exercises in
single sessions) were found. One study 
demonstrated a significant decline in TLR4, and the other [
did not find a difference in TLR4 (Table 8).
The Timmerman et al. [
] study analyzed the
response of 12 weeks of exercise training on the part of
aged, physically inactive subjects who performed AE for
20 min and RE for 30 min. No significant differences in
TLR4 (protein expression) were found in the trained
group compared to the controls, but a decline in TNF-α
was observed. Stewart et al. [
] compared CE effects in
adult and aged participants and showed a significant
decline in TLR4 as well as IL-6 in the physically inactive
groups compared to controls; however, levels of TLR2
were not significantly changed.
Another experiment [
] verified a decline in CRP in
both trained and active control groups and concluded
that AE and RE may be applied in the same session as a
potential therapeutic intervention for adults and aged
individuals to avoid some chronic diseases. Therefore, this
review suggests that AE and RE in combination protect
against the negative effects of AE.
Exercise, Disease, and Inflammation
The majority of the studies eligible for this review show
that both AE [
13–15, 113–115, 117
] and RE [
act as excellent auxiliary treatments for chronic disease.
However, we found no article that tested ARE in samples
from patients with diseases.
One of the important features of obesity-induced
inflammation is a phenotypic change in the populations of
macrophages and T cells present in the adipose tissue.
This is reflected in levels of the production of anti- and
pro-inflammatory cytokines [
]. It has been suggested
that free saturated fatty acids can induce inflammation
3 days/week, 70–80% 1 RM and 50–70%
of heart rate reserve, 12 weeks
3 days/week, 70–80% 1 RM and 70–80%
of heart rate reserve, 12 weeks
↓TLR4, ↔TLR2 ↔TNF-α
through the activation of macrophages, TLR2, and TLR4
in the adipose tissue, culminating in the activation of
NF-kB and an increased expression of pro-inflammatory
cytokines such as TNF-α or IL-6 [
7, 9, 151
The study by Phillips et al. [
] in post-menopausal
obese women showed that CRE did not decrease TLR4
in terms of mRNA expression but reduced inflammatory
markers such as TNF-α and IL-6. In another study
related to obesity, 10 days of either moderate (MICT) or
high intensity (HIIT) CAE in inactive overweight women
promoted improvements in glucose control and
cardiorespiratory capacity and a decrease in TLR2 and TLR4
(protein content) [
Most studies in this review that tested the levels of
TLR2 and/or TLR4 receptors in a disease context used
moderate load protocols, with the exception of the study
by Nickel et al. [
], which studied marathon runners
and found an increase in the mRNA expression and
protein levels of these receptors. In this study, TLR2 was
significantly increased in lean-non-elite athletes when
compared to the obese-non-elite and lean-elite groups,
and TLR4 increased in all groups in response to
exercise. However, levels of the systemic cytokines TNF-α
and IL-6 remained stable. Interestingly, oxidized
lowdensity lipoprotein (oxLDL) levels in obese athletes were
reduced and associated with higher adiponectin levels,
in contrast to increased levels of oxLDL found in the
group of lean-elite athletes [
]. This can be
understood from the fact that TLR4 plays a crucial role in
cellular responses to oxLDL exposure and the activation of
]. Wang et al.  showed that the
activation of the TLR4/NF-κB signaling pathway was a
potential mechanism for oxLDL-induced apoptosis in
Higher levels of this low-density lipoprotein (LDL) are
usually associated with an increased risk for
], and marathon runners may, in fact, have
increased levels of atherosclerosis [
]. LDL, when
modified by enzymes such as phospholipases, gives rise
to oxidized low-density lipoprotein (oxLDL), which
contributes to the formation and progression of
atherosclerotic plaques [
]. oxLDL is known to be
immunogenic and activates endothelial cells, monocytes,
macrophages, and T cells . Furthermore, oxLDL is
toxic at higher concentrations and thus could be a cause
of cell death in lesions [
]. The plasma level of oxLDL
was shown to be a predictor of mortality in patients with
chronic congestive heart failure [
] and induced severe
cell damage in ventricular myocytes [
This review also found articles that generally analyzed
TLR2 and/or TLR4 expression in relation to other
diseases. The study by Zwagerman et al. [
], for example,
found that in addition to reduced levels of TLR4 (gene
and protein), CAE reduced the frequency of cerebral
infarction. Another study [
] analyzed chronic fatigue
syndrome in acute AE sessions at moderate intensity for
25 min. In addition to an increase in the mRNA
expression of TLR4 and pro-inflammatory cytokines,
symptoms such as pain and physical and mental fatigue
became worse after exercise, suggesting a dysregulation
of the immune and sympathetic nervous systems.
This is the first systematic review of the literature that
addresses the roles of TLR2 and TLR4 receptors in
various types of exercise. Our main finding is evidence for
an accentuation in the inflammatory processes
orchestrated by these receptors in both AAE and CAE. The
results also suggest that the expression of the receptors is
correlated with that of anti- and pro-inflammatory
cytokines. Taken together, these data open new perspectives
for studies aimed at a better understanding of the
response of inflammatory processes to physical exercise.
An analysis of the pathways involving TLR2 and TLR4
reveal something about the way specific types of physical
exercise are related to differences in the types of
inflammatory responses they stimulate. The results indicate that
AE is potentially inflammatory; a smaller number of
studies revealed that acute exercise has anti-inflammatory
effects, compared to studies of chronic exercise.
Our analysis showed that in RE, TLR2 and TLR4
expression and signaling adopt an anti-inflammatory
pattern. Studies that met our criteria for inclusion indicated
that acute or chronic sessions reduced TLRs as well as
inflammatory cytokines, particularly TNF-α, and
promoted increases in IL-10, which can be considered a
beneficial adaptation for both healthy people and those
affected by certain diseases.
The same results were obtained when differences in
the populations and intensities of exercise were taken
into account. This indicates that RE can be broadly used
to prevent or minimize the potentially deleterious effects
of TLR expression and that the intensity can be
manipulated to achieve other goals, such as increasing body
strength, without a loss of benefits vis-à-vis the overall
For AE, the intensity of exercise is a crucial
factor—better responses were achieved under moderate intensities.
But overall, whether the effects of AE will be positive or
negative depends on a person’s other physiological
characteristics, so they must be taken into account.
Generally, CE seems to be a good choice in most
situations due to its positive effects on TLR expression and
signaling. In other words, the possible negative “side
effects” of AE can be overcome through the positive
impact of RE. This combination of training strategies
appears to improve a person’s general inflammatory
profile while maintaining the cardiovascular and metabolic
benefits of AE. In most cases, this leads to better
adaptations. But because the number of studies addressing the
effects of TLR2 and TLR4 in CE is very small, further
research is needed for both amateurs and elite athletes.
AAE: Acute aerobic exercise; AE: Aerobic exercises; ARE: Acute resistance
exercise; Arg1: Arginase-1; CAE: Chronic aerobic exercise; CE: Combined
exercise; CK: Creatine kinase; CRE: Chronic resistance exercise; CRP: C-reactive
protein; DAMPs: Damage-associated molecular patterns; IGF-1: Insulin-like
growth factor 1; LPS: Lipopolysaccharides; MAPK: Mitogen-activated protein
kinase; PAMPS: Pathogen-associated molecular patterns; RE: Resistance
exercise; ROS: Reactive oxygen species; TLR: Toll-like receptor; TLR2: Toll-like
receptor 2; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor alpha;
VEGF: Vascular endothelial growth factor
We thank Russ Hodge for assisting in writing the manuscript.
Availability of Data and Materials
PAMC: substantial contributions to the conception; design and drafting of
the work; survey of the literature; preparation of tables and creation of
figures; analysis; interpretation of data; critical review. MFG: contributions to
the conception; review of tables; analysis; critical review. JSH: contributed to
the analysis; English translation; critical review. FHO: contributions to the
conception; analysis; critical review. RCA: contributions to the conception;
analysis, interpretation of data; critical review. All authors read and approved
the final manuscript.
The authors have received no payment or services from a third party for any
aspect of the submitted work.
PAMC: Ph.D. Student in Medicine (Nephrology) Program at Federal University
of São Paulo, Department of Biophysics at Federal University of São Paulo,
and Laboratory of Exercise Genetics and Metabolism at Federal University of
São Paulo (UNIFESP), São Paulo, SP, Brazil with a collaborative period in
Berlin, Germany at Max-Delbrück-Centrum für Molekulare Medizin; Master of
Physical Education at São Judas Tadeu University, São Paulo, SP, Brazil. MFG:
Ph.D. Student in Molecular Biology Program at Federal University of São
Paulo, Department of Biophysics at Federal University of São Paulo, and
Laboratory of Exercise Genetics and Metabolism at Federal University of São
Paulo (UNIFESP), São Paulo, SP, Brazil; Master of Molecular Biology at Federal
University of São Paulo, São Paulo, SP, Brazil. JSH: Master Degree Student in
Neurology/Neuroscience Program at Federal University of São Paulo and
Exercise Neurophysiology Laboratory at Federal University of São Paulo
(UNIFESP), São Paulo, SP, Brazil; Graduation in Physical Education at University of
Santos (UNIMES), São Paulo, SP, Brazil. FHO: Ph.D. Student in Medicine
(Nephrology) Program at Federal University of São Paulo, Department of Biophysics
at Federal University of São Paulo, and Laboratory of Exercise Genetics and
Metabolism at Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil;
Master of Health Sciences at Faculty of Medical Sciences of Santa Casa
(FCMSCSP), São Paulo, SP, Brazil. RCA: Post-doctorate in Biological Sciences at
Federal University of São Paulo (UNIFESP), SP, Brazil; Ph.D. in Biological
Sciences (Molecular Biology) at Federal University of São Paulo (UNIFESP), SP,
Brazil with a collaborative period in Berlin, Germany at
Max-Delbrück-Centrum für Molekulare Medizin; Master of Biological Sciences (Physiology and
Pharmacology) at Federal University of Minas Gerais (UFMG), MG, Brazil. He is
currently a professor of the Biophysics Department of the Federal University
of São Paulo (EPM). He has an experience in the field of Biophysics, working
mainly on the following subjects: physical exercise, obesity, kinins, transgenic
animals, kallikrein, inflammation, and blood pressure.
Ethics Approval and Consent to Participate
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Paula Andréa Malveira Cavalcante, Marcos Fernandes Gregnani, Jessica Salles
Henrique, Fábio Henrique Ornellas, and Ronaldo Carvalho Araújo declare that
they have no conflicts of interest related to this manuscript.
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