Edited by: Evangelos A. Christou, University of Florida, USA
Reviewed by: Alvaro N. Gurovich, Indiana State University, USA; Fan Ye, University of Florida, USA
*Correspondence: Eric J. Downer
This article was submitted to Exercise Physiology, a section of the journal Frontiers in Physiology
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Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.
Multiple Sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS; Calabresi,
The pathogenesis of MS is highly complex with the identity of a single unifying cause underlying its etiology remaining elusive; however it is believed that an intricate interplay between immunological factors, genetic factors and environmental influences determines susceptibility to the disease (Figure
Historically, MS has been regarded as an adaptive immune response through the activation of autoreactive myelin specific T-cells, for example activation of autoreactive CD4+ T cells and their differentiation into T-helper 1 (Th1) cells is of particular importance in MS (Fletcher et al.,
Currently available immunomodulatory therapies for MS include injectable medications such as interferon (IFN)-β (betaseron®, extavia®, avonex®, rebif®) and glatiramer acetate (copaxone), oral medications such as fingolimod (gilenya®) dimethyl fumarate (tecfidera®) and teriflunomide (aubagio®), and infused medications such as natalizumab (tysabri®), alemtuzumab (lemtrada™), and mitoxantrone (novantrone®; Table
Beta interferon 1a | Avonex®, Rebif® | Intramuscular/Subcutaneous | Downregulates T cell activity and inflammatory cytokines |
Beta interferon 1b | Betaseron® | Subcutaneous | Downregulates T cell activity and inflammatory cytokines |
Glatiramer acetate | Copaxane | Subcutaneous | Inhibits MBP reactive T cell activation and increases Th2 cell population |
Fingolimod | Gilenya® | Oral | Prevents lymphocyte egress from lymph nodes |
Dimethlyfumarate | Tecfidera® | Oral | Inhibits expression of cytokine and inflammatory molecules |
Alemtuzumab | Lemtrada™ | Infused | Depletes circulating lymphocytes |
Natalizumab | Tysabri® | Infused | Blocks lymphocyte migration into the CNS |
Teriflunomide | Aubagio® | Oral | Inhibits DHODH & reduces lymphocyte proliferation |
Mitoxantrone | Novantrone® | Infused | Targets T/B cell activity and macrophage proliferation |
Avonex® and rebif® (both IFN-β-1a), and betaseron® and extavia® (IFN-β-1b), exert effects on the BBB and the activity of lymphocytes (Mendes and Sá,
Gilenya® modulates sphingosine-1 phosphate receptor activity resulting in prevention of lymphocyte egress from lymph nodes (Matloubian et al.,
Tysabri® is a monoclonal antibody that therapeutically modulates immune responses in MS. Tysabri® has specificity for the α4-integrin receptor subunit on activated T cells, antagonizes cell adhesion to vascular endothelium at the BBB, and hence inhibits immune cell infiltration into the CNS (Yednock et al.,
Playing an essential role in immunity, the innate immune system is recognized as the first line of host defense, providing immediate protection against pathogenic infectious agents through initiating complex interactions between the pathogen and the immune mechanisms of the host (Kumar et al.,
TLRs are a family of innate immune system receptors which either span the cell membrane or are expressed intracellularly on endosomes in both nonimmune and immune cells (Figure
TLR1 | Extracellular | Bacteria: peptidoglycan | Pam3CSK4 | |
TLR2 | Extracellular | Bacteria: lipoproteins | Heat shock | Pam3CSK4, MALP-2 |
Fungi: zymosan | HMGB1,veriscan | |||
TLR3 | Intracellular | Virus: dsRNA | mRNA | Poly(I:C) |
TLR4 | Extracellular | Bacteria: LPS | Saturated fatty acids | Lipid derivatives |
Virus: fusion protein | Amyloid-β | |||
Fungi: mannan | ||||
TLR5 | Extracellular | Bacteria: flagellin | ||
TLR6 | Extracellular | Bacteria: lipoteichoic acid | Veriscan | |
TLR7 | Intracellular | Virus: ssRNA | Self RNA | Imidazoquinoline, Bropirimine |
TLR8 | Intracellular | Virus: ssRNA | Self RNA | Imidazoquinoline, |
TLR9 | Intracellular | Bacteria: CpG- DNA | Self RNA | CpG-ODN |
Virus: CpG- DNA | ||||
TLR10 | Extracellular | Virus: H5N1, H1N1 |
TLRs are type 1 transmembrane proteins and are comprised of a cytoplasmic Toll/IL-1R (TIR) domain and an extracellular leucine-rich repeat (LRR) domain (Singh and Naik,
All TLR (apart from TLR3) signaling involves the recruitment of a key adaptor protein, myeloid differentiation factor 88 (MyD88). Additional adaptor proteins, including MyD88-adapter-like (MAL) and TRIF-related adaptor molecule (TRAM) both act as bridging adaptors, with MAL facilitating the interaction of MyD88 with TLR4 to promote NF-κB activation, whereas TRAM recruits the adaptor protein Toll/IL-1R domain-containing adaptor inducing IFN (TRIF) which enables IRF-3 activation (O'Neill and Bowie,
TLR4 is localized on the cell surface of immune cells and cells of the CNS, and is activated primarily to bacterial PAMPS such as gram negative bacteria lipopolysaccharide (LPS). Recognition also requires the accessory molecule MD2 (Kim et al.,
TLR3 resides in endosomal compartments of immune (particularly in DC and B cells) and CNS cells, and recognizes distinct viral double stranded nucleic acid RNA (Singh and Naik,
Infections have been thought to increase susceptibility to autoimmune diseases. For example, many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS (Lünemann et al.,
MS is driven by pro-inflammatory chemokines and cytokines (Sørensen et al.,
Infiltrating and resident cells within the CNS both express TLRs and an increase in TLR expression has been observed in autoimmune diseases such as MS (Miranda-Hernandez and Baxter,
Using experimental autoimmune encephalomyelitis (EAE), the murine model of MS, specific roles of TLRs have been indicated in EAE. Indeed, stimulation of TLR3 with poly(I:C) has been demonstrated to suppress the development of a murine model of relapsing EAE, presumably through enhanced levels of IFN-β and the chemokine, CCL2 (Touil et al.,
Alternatively, TLR signaling through the MyD88-dependent pathway is believed to play a part in the development of EAE. Indeed, Marta et al. (
Pertussis toxin (PT) administered at the time of immunization is suggested to regulate P-selectin expression and enhance leukocyte/endothelial cell interactions, facilitating T cell infiltration into the CNS by increasing BBB permeability. PT induces TLR4 signaling and consequently controls leukocyte recruitment in wild type mice. These effects were not detected in TLR4 knockout mice and they were less susceptible to PT-induced EAE in comparison to wild type mice (Kerfoot et al.,
Differential TLR responses of immune cells isolated from MS patients also suggest the complex role of TLR signaling in MS pathogenesis. Indeed, Crowley et al. (
Exercise activates an array of immunological and hormonal responses, and much evidence indicates that exercise training can ameliorate chronic neuroinflammation and its related pathologies by targeting pro- and anti-inflammatory cytokines (Florindo,
Acute exercise can profoundly affect immune cell profiles, particularly during and immediately after exercise. Indeed, marathon running enhances the circulating DC population, while decreasing the number of plasmacytoid DC, in healthy elite and non-elite runners, suggesting that immunomodulatory mechanisms are central in the response to acute excessive exercise (Nickel et al.,
It is important to note that several studies indicate that acute exercise reduces innate immune receptor expression, and may account for post-exercise immuno-depression. Indeed, marathon running reduces the expression of TLR7 on PBMCs (Nickel et al.,
A body of literature in human trials indicates the impact of chronic exercise on cytokine and inflammatory signaling networks may have a dose-dependent relationship with exercise intensity. Indeed, the immunomodulatory effect of repeated bouts of exercise is well characterized. Resistance training (72 exercise sessions over 6 months) in healthy elderly women reduces TLR4 expression on monocytes (McFarlin et al.,
It is well known that exercise is anti-inflammatory and promotes neuroregeneration, plasticity and memory in rodents (Bechara et al.,
Overall, an imbalance between pro- and anti-inflammatory cytokines exists in MS, exhibiting a shift toward a pro-inflammatory cytokine profile. This makes pro-inflammatory cytokines a good therapeutic target. Numerous sources have indicated that regular exercise can reverse chronic inflammation, with evidence indicating that physical activity decreases pro-inflammatory cytokines as well as promoting an increase in anti-inflammatory cytokines. Indeed in MS, evidence suggests that regular exercise can induce anti-inflammatory effects and may be beneficial in the modulation of MS progression (Figure
Using EAE, the murine model of MS, several studies have indicated that exercise can combat the clinical development of the disease (Rossi et al.,
In MS patients, Golzari et al. (
In addition to the alterations in inflammatory signature, physical activity is proposed to target multiple clinical manifestations in MS; however the optimal exercise prescription has not yet been established for MS patients. A body of data illustrates that physical activity is an effective strategy for overall health, which is accessible to most individuals and is without any intolerable side effects that generally coexist with pharmaceutical treatment. Indeed, Learmonth et al. (
Mobility is a critical concern for individuals with MS, interfering with performance in daily living activities. A high prevalence rate of falls also occurs among MS patients (Finlayson et al.,
Briken et al. (
Fatigue, a debilitating symptom experienced by most MS patients, further disrupts aspects of everyday activities and interferes with normal life. While the effect of exercise on fatigue in MS patients remains unclear, improvement in fatigue appears to depend on the type of exercise. In one study, analysis suggested that a decrease in fatigue (as determined using visual analog scales) emerged in MS patients after a single bout (15 min) of aerobic cycling (Learmonth et al.,
Anxiety and depression are elevated amongst MS patients in comparison to healthy individuals (McCabe,
Cognitive disturbances affect ~40–65% of MS patients (Rao et al.,
MS is a chronic disease accounting for lasting disability among young adults and hence MS rehabilitation is essential for patients to maintain an independent lifestyle and to ensure an improved quality of life. Originally MS patients were advised to avoid exercise since elevated body temperature was suggested to exacerbate symptoms, as observed by Uhthoff (Humm et al.,
There is no cure for MS, with a number of approved medications in the clinic demonstrating proclivity to reduce frequency of relapses and long-term accrual of disability. The observation that disability often continues to worsen despite immunotherapy has prompted some MS patients to seek alternative treatments for the disease. Since MS is an immune-mediated disease and MS patients demonstrate a shift toward a pro-inflammatory signature, neuro-immune signaling represents a clear therapeutic target. Recent data suggests the potential role of the innate immune system in the initiation and progression of MS, and also indicates that exercise may modulate the innate immune system by directly targeting TLR signaling events. Given these findings, characterizing the impact of aerobic exercise on the expression profile of TLRs and associated inflammatory cytokines linked with MS neuropathology requires full investigation. Such investigation will elucidate the clear biological basis for exercise in MS, and will furthermore assist in delineating the therapeutic potential of exercise training in individuals afflicted by the disease.
ED and KO funded the project. ED and AB wrote the manuscript. OC, AR, BS, SY, OO, AA, GC, and KO critiqued and edited the manuscript drafts.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the Physiological Society, Department of Physiology, University College Cork and the Department of Physiology, Trinity College Dublin.