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Table of Contents
Year : 2020  |  Volume : 63  |  Issue : 6  |  Page : 250-255

Long-term aerobic exercise training-induced anti-inflammatory response and mechanisms: Focusing on the toll-like receptor 4 signaling pathway

1 College of Human Development and Health, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
2 College of Human Development and Health; Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
3 Department of Emergency, Taipei Veterans General Hospital; Department of Emergency Medicine, School of Medicine, National Yang-Ming University, Taipei; Kinmen Hospital, Ministry of Health and Welfare, Kinmen, Taiwan
4 Department of Physiology, School of Medicine, National Yang-Ming University; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

Date of Submission10-Oct-2020
Date of Decision13-Nov-2020
Date of Acceptance16-Nov-2020
Date of Web Publication26-Dec-2020

Correspondence Address:
Prof. Chi-Chang Juan
Department of Physiology, School of Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 112304
Dr. Chorng-Kuang How
Department of Emergency, Taipei Veterans General Hospital, No. 201, Section 2, Shi-Pai Road, Taipei 112201
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CJP.CJP_78_20

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Toll-like receptor 4 (TLR-4), which regulate inflammatory reactions, has become a popular research topic in recent years. This article reviews the latest scientific evidence on the regulation of TLR-4 by regular aerobic exercise training. The literature shows that long-term regular aerobic exercise training can effectively attenuate the expression of TLR-4 in immune cells and regulate its downstream intracellular cascade, including the p38 and PI3K/Akt signaling pathways. This further reduces cytokines secretion by inflammatory cells, which enhances immune system. We consider that the scientific evidence that long-term aerobic exercise training improves the inflammatory response provides a reasonable basis for using aerobic exercise training as a treatment for patients.

Keywords: Aerobic exercise training, inflammatory response, p38, PI3K/Akt, toll-like receptor 4

How to cite this article:
Chen CW, Kuo YC, How CK, Juan CC. Long-term aerobic exercise training-induced anti-inflammatory response and mechanisms: Focusing on the toll-like receptor 4 signaling pathway. Chin J Physiol 2020;63:250-5

How to cite this URL:
Chen CW, Kuo YC, How CK, Juan CC. Long-term aerobic exercise training-induced anti-inflammatory response and mechanisms: Focusing on the toll-like receptor 4 signaling pathway. Chin J Physiol [serial online] 2020 [cited 2022 Aug 17];63:250-5. Available from: https://www.cjphysiology.org/text.asp?2020/63/6/250/304860

  Introduction Top

In 1996, Jules Hoffmann, a Luxembourg-born French biologist, discovered the Toll protein in Drosophila.[1] Two years later, Bruce Beutler, an American immunologist and geneticist, identified toll-like receptors (TLRs) in mice.[2] Due to the significance of this discovery, these two scientists both won the Nobel Prize in Physiology and Medicine in 2011. The discovery was significant because of the critical role of TLRs in immunology regulation and the awarding of the Nobel Prize emphasized this fact.

In addition, it is widely recognized that exercise is one of the crucial factors for improving and maintaining physical function and health. From an immunological perspective, exercise training can reduce the risk of infection,[3],[4] increase the phagocytic capacity of macrophages,[5] and enhance the activity of antioxidant enzymes in intestinal lymphocytes.[6] Thus, exercise training is a well-known nonpharmacological approach to regulating the immune system. Many research confirms that exercise training is indeed a critical regulator of both innate and acquired immunity.[3],[4] In sports and exercise science, with the development of medical technology and measurement systems/skills, the molecular mechanisms by which exercise improves the immune response can now be observed at the intracellular level.[7],[8],[9] This article provides an in-depth discussion on the signaling transduction pathway through which long-term aerobic exercise training regulates the immune response. To do this, we review the literature that provides scientific evidence of the critical role of long-term aerobic exercise training in the anti-inflammatory process.

  Toll-Like Receptors Top

The toll protein or toll receptor – a unique protein first discovered in Drosophila – is mainly involved in the protection against fungal infections.[1] In 1997, Medzhitov et al. discovered the human homologs of the toll receptor in immune cells such as monocytes, macrophages, and T- and B-lymphocytes and named them TLRs.[10] TLRs are type 1 transmembrane proteins and play an essential role in the identification and defense of pathogens by the immune system.[11],[12]

Innate immunity is the first defense mechanism against foreign pathogens in the host's body. The structure and components of the pathogens activate signaling pathways in the immune cells, which initiates the innate immune response, promotes the synthesis of inflammatory mediators, and enhances phagocytosis.[13] TLRs are a type of pattern-recognition receptor that can recognize specific structures on microorganisms, such as lipoproteins, peptidoglycans, or flagella, to identify the source of exogenous infection. These structures are collectively referred to as pathogen-associated molecular patterns (PAMPs).[14] TLRs initiate the intracellular molecular signaling pathway when they recognize PAMPs. This leads to the phosphorylation of the inhibitory protein IκB, result in its ubiquitination and dysfunction. Hence, translocation of nuclear factor kappa B (NF-κB) into the nucleus for transcription,[15],[16] which promotes the production of cytokines synthesize and initiates the innate immune system.[17]

At present, 12 different types of TLR are known in mammals.[14] The fourth type, TLR-4, was the first to be discovered and is the most important and most thoroughly studied of the TLRs. Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, is the most common ligand of TLR-4.[13],[14] The combination of TLR-4 and LPS initiates and activates the molecular signaling pathway of immune cells to promote the secretion of tumor necrosis factor-alpha (TNF-α), interleukin (IL) 1, IL-6, IL-12, nitric oxide (NO), eicosanoids, and other inflammatory molecules.[14] Although these reactions are critical for the protection against infectious microorganisms, excessive secretion of inflammatory molecules can induce septic shock,[14],[17] asthma,[18],[19] rheumatoid arthritis,[20],[21] intestinal inflammatory diseases,[21] lung injury,[22] and even death in severe cases. Therefore, the binding of TLR-4 with LPS is also regarded as a “danger signal.”[23]

  Toll-Like Receptor 4 Activation and Downstream Signaling Top

The binding reaction of TLR-4 and LPS initiates the inflammatory response. The first step in the signaling pathway is the polymerization of myeloid differentiation factor 88 (MyD88), an adaptor protein.[24] The inflammation signal is then transmitted to downstream signaling cascade, which activates IκB and mitogen-activated protein kinases (MAPKs). These two activation pathways continuously promote the activation of the downstream transcription factors NF-κB and activator protein 1 (AP-1),[25],[26] leading to the regulation and overexpression of inflammatory cytokine genes. This ultimately results in the secretion of synthetic inflammatory proteins by the cell, to produce an immune response.

The MAPKs include c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38. Any activation of MAPK proteins can cause inflammation. Furthermore, in addition to the regulation of the secretion of TNF-α[8],[27],[28] and IL-6[8],[28] that is induced by LPS, p38 can enhance the expression of inducible NO synthase (iNOS) in the nucleus of macrophage. The increased expression of iNOS promotes the secretion of NO.[29] NO is also classified as an inflammatory molecule, since it plays roles in the host defense, antimicrobial infection, and tumor-causing-cell-death functions of the immune system.[30] Similar to p38, the ERK protein can also stimulate the synthesis of NO[31] and cytokines.[32] It has further been shown that LPS can activate downstream transcription factors such as AP-1 and NF-κB to cause over-production of inflammatory mediators.[33] It does this by stimulating the phosphorylation of inflammatory signal such as JNK, ERK, and p38 in the immune cells. Conversely, inhibition of the phosphorylation of MAPKs reduces inflammation.[34],[35],[36],[37],[38] The relationship between pathways involving MAPKs and the inflammation response is thus clear.

In terms of intracellular molecular signaling, TLR-4 can also regulate the immune response by activating the downstream PI3K/Akt pathway. In 2002, Fukao et al. suggested the critical regulatory role of PI3K in the inflammation response. They used PI3K knock-out mice (PI3K−/−) as an experimental model and found that the expression of IL-12 induced by the dendritic cells in LPS-induced PI3K−/− mice was significantly higher than in LPS-induced normal mice (PI3K+/+).[39] Furthermore, administration of the PI3K inhibitor wortmannin had been found promotion LPS-evoked IL-12 secretion in the dendritic cells of normal mice (approximately five-fold).[39] Subsequently, Fukao et al. also observed that PI3K−/− mice were weak against infection from intestinal nematode.[40] In the same year, Guha and Mackman found that inhibiting the PI3K/Akt pathway in human monocytes caused massive translocation of NF-κB into the nucleus and promoted the TNF-α secretion,[41] in addition to enhancing the expression of MAPKs. Since this important finding contradicted the established understanding and suggested a novel molecular downstream pathway of TLR-4 that regulates the inflammation response, Fukao and Koyasu published a comprehensive review of the scientific evidence in 2003, proposing that the PI3K protein can negatively regulate the downstream signaling pathway of TLR-4.[42] This review focused mainly on the immunosuppressive effect of PI3K/Akt activation, but also suggested that it could decrease the expression of MAPKs, resulting in anti-inflammation.

This concept is supported by increasing scientific evidence. Giving PI3K inhibitors to mice with polymicrobial sepsis induced by cecal ligation and puncture significantly increased their mortality.[43] Other studies also found that giving PI3K inhibitors to TLR-4−/− mice caused more severe inflammation and higher mortality than in nontreated TLR-4−/− mice.[44] All this evidence thus suggests that PI3K plays a critical protective role in the immune system. Furthermore, many in vitro experiments have shown that activation of the PI3K/Akt pathway can indeed attenuate LPS-induced inflammatory response, including by blunting the activity of NF-κB[41],[45] and the expression or secretion of the inflammatory cytokines.[41],[45],[46],[47] Other clinical studies have shown that inhibiting the PI3K/Akt pathway affects the anti-inflammatory cytokine IL-10 secretion, changing the anti-inflammatory effect.[48] The TLR-4-related signaling pathways are shown in [Figure 1].
Figure 1: Schematic overview of toll-like receptor 4 downstream signaling pathway. Toll-like receptor 4 ligands bind to toll-like receptor 4 on the cell membrane, leading to the activation of myeloid differentiation factor 88 signaling pathway. The myeloid differentiation factor 88 pathway signals through activation mitogen activated protein kinase and phosphoinositide 3-kinase signaling, which in turn leads to regulation of transcription factors nuclear factor-κB and activator protein-1, respectively, and mediates the inflammatory cytokines secretion.

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  Anti-Inflammatory Effects and Molecular Mechanisms of Long-term Aerobic Exercise Training Top

As a result of the rapid development of technology in sports science and immunology, the mechanisms by which exercise training regulates the immune response can now be observed in detail, at the cellular and molecular levels. Evidence confirms that regular exercise training can have anti-inflammatory properties by diminishing the secretion of cytokines, which affects various immune cells, such as macrophages,[8] lymphocytes,[6],[49] and spleen cells.[7],[50] This effect may be related to the expression of TLR-4 at the cellular level. Early studies focused on the benefits of resistance exercise in particular. Flynn et al. found that the expression level of TLR-4 mRNA in monocytes from women who had undergone resistance exercise training was significantly lower than control group.[51],[52] Therefore, lower secretion level of LPS-induced inflammatory cytokines in the group who received resistance exercise training.[51] Further, Stewart et al. found that when people who had formerly had a sedentary lifestyle received 12 weeks of long-term exercise training, including endurance and resistance training program, the TLR-4 expression in the CD14+ immune cells in their blood decreased significantly.[53] This suggests that TLR-4 expression can be changed through regular exercise training/physical activity. As mentioned in the previous research, Ma et al. first used a rat stroke model to induce an increased level of TLR-4 in the brain. The rats were given 3 days, 7 days, and 2 weeks (20 m/min, 60 min/day, and 5 day/week) aerobic treadmill exercise training as a treatment, and changes in the inflammation pathway in their brains were observed.[54] Ma et al. found that regular aerobic exercise training reduced the overexpression of TLR-4 that is induced by stroke, as well as the expression of downstream factors from the TLR-4 signal, such as MyD88 mRNA and the NF-κB p65.[54] In a recent study, similar results have been demonstrated in hippocampus, where 8-week treadmill aerobic exercise training (10 m/min, 60 min/day, and 6 day/week) intervention diminished the TLR-4, MyD88, and NF-κB p65 expressions in depressed mice.[55] Based on these findings, sports immunologists have suggested that regular exercise training can inhibit the expression of TLR-4.[56],[57] This implies that regular exercise training can suppress the expression of dangerous signals and have anti-inflammatory properties.

In recent years, taking regular exercise has become a common practice, and long-term regular aerobic exercise training has come to be considered a practical prescription for improving immunity.[58],[59] Sports scientists have therefore focused on investigating the mechanisms by which aerobic exercise regulates the immune system. Although studies have shown that, long-term regular aerobic exercise training can blunt TLR-4 expression[54],[55],[60] and have anti-inflammatory effects, no studies have yet investigated this effect in professional immune cells specifically. The implications of these findings should therefore be inferred with caution. With respect to the professional immune cells, Chen et al. found in 2010[8] that long-term regular aerobic exercise training (60% VO2max, 60 min/day, 5 day/week for 8 weeks) can inhibit the p38 phosphorylation in specific immune cell (macrophages). Following in vivo injection of LPS, the concentrations of TNF-α and IL-6 secretions were significantly reduced, by more than 50% in macrophage.[8] However, Chen et al. did not test any proteins in the MAPK signaling pathway except for p38. Therefore, the mechanism by which exercise training regulates TLR-4 downstream signaling in specific immune cell is not fully understood.

The PI3K/Akt signaling pathway, which is thought to negatively regulate the inflammatory response induced by TLRs, is also downstream of TLR-4.[42] Martin et al. found that attenuating the expression of PI3K or Akt caused increased release of IL-12 under LPS stimulation and reduced synthesis of IL-10, an anti-inflammatory cytokine.[61] Based on previous findings, Chen et al. found that, in rat professional immune cells (splenocytes), treadmill aerobic exercise training (20 m/min, 30 min/day for 7 days) not only inhibited the expression of TLR-4 but also activated the phosphorylation of PI3K/Akt.[7] The activation PI3K/Akt signal immediately diminished the phosphorylation of NF-κB, leading to a significant reduction in cytokine secretion and resulting in anti-inflammatory effects.[7] This study speculates that regular aerobic exercise training could cause a novel adaptation phenomenon in the immune system, in which decreased expression of TLR-4 in specific immune cells, followed by the promotion of the PI3K/Akt signaling pathway, results in reduced synthesis and release of inflammatory molecules.[7] These results are schematically illustrated in [Figure 2].
Figure 2: Schematic representation of the cellular model for the inhibitory effect of long-term aerobic exercise training on the toll-like receptor 4 and downstream intracellular signaling pathway. Aerobic exercise training inhibited toll-like receptor 4 expression, and subsequently downregulated p38 activation or promotion phosphoinositide 3-kinase/Akt expressions, which in turn decreased nuclear factor-κB expression, leading to attenuated inflammatory cytokines secretion.

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  Conclusion and Future Perspectives Top

Maintaining a habit of regular exercise training is thus the most important factor in improving and maintaining physical health. In sports and exercise science, knowledge about the positive effects of regular exercise training on the immune system has increased as a result of numerous studies conducted in the last few years. This article clarifies the critical role of long-term regular aerobic exercise training in regulating immune function. Specifically, such exercise training affects various molecular pathways to moderate the secretion of inflammatory cytokines by immune cells, resulting in a reduced inflammatory response. The scientific evidence reviewed here suggests effective therapeutic strategies for preventive medicine. However, the mechanism by which the signaling pathways downstream of TLR-4 regulate the professional immune cells has not yet been thoroughly investigated. It is also not yet clear whether regular aerobic exercise training is similarly effective in a range of diseases. This review thus suggests new directions and perspectives for future research to explore.

Financial support and sponsorship

This work was supported by the grants from National Taipei University of Nursing and Health Sciences (109ntunhs-NT-04), and “Yin Yen-Liang Foundation Development and Construction Plan” of the School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Conflicts of interest

There are no conflicts of interest.

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