Inflammatory Role of TLR-MyD88 Signaling in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a neuro-autoimmune and neurodegenerative disorder leading to chronic inflammation, demyelination, axonal, and neuronal loss in the central nervous system (CNS). Despite intense research efforts, the pathogenesis of MS still remains unclear. Toll-like receptors (TLRs) are a family of type I transmembrane receptors that play a crucial role in the innate immune response. Myeloid differentiation factor 88 (MyD88) is the adaptor of major TLRs. It has been widely considered that the TLR-MyD88 signaling pathway plays an important role in the occurrence and development of autoimmune disease. Data have revealed that the TLR-MyD88 signaling may be involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model for MS, by regulating the antigen presentation of dendritic cells, the integrity of blood-brain barrier (BBB), and the activation of T cells and B cells. Here, we summarize the role of TLRs and MyD88 in MS and discuss the possible therapies that are based on these molecules.

TLR-mediated activation of peripheral blood monocyte phagocytosis in patients with multiple sclerosis

“…We have shown that activation of the Fc receptor of mononuclear cells by ssRNA40/LyoVec was stronger compared to the stimulating effect of LPS, possibly related to the involvement of a subpopulation of "non-classical" monocytes in phagocytosis. Clarification of the role of peripheral blood monocytes in the pathogenesis of the disease, determination of appropriate immunophenotypes, according to some researchers may be of practical importance, in particular to be one of the criteria for predicting the effectiveness of therapy for stratification of patients with multiple sclerosis [4,7,9,18,19]. Zheng S. et al have found out that the dysregulation of TLR7/8 signals on mononuclear cells may be considered as one of the key factors in the development of neuroinflammation in multiple sclerosis [7].…”

“…Clarification of the role of peripheral blood monocytes in the pathogenesis of the disease, determination of appropriate immunophenotypes, according to some researchers may be of practical importance, in particular to be one of the criteria for predicting the effectiveness of therapy for stratification of patients with multiple sclerosis [4,7,9,18,19]. Zheng S. et al have found out that the dysregulation of TLR7/8 signals on mononuclear cells may be considered as one of the key factors in the development of neuroinflammation in multiple sclerosis [7]. Hurtado-Guerrero I. et al have demonstrated that TLR7 signaling mechanisms are disturbed in peripheral blood monocytes in patients with recurrent remitting disease [19].…”

“…Stimulation of TLRs of different types by agonists specific to them causes activation of the signaling pathway cascade, which in turn leads to the development of general and subpopulation-dependent functional reactions inherent in peripheral blood monocytes. It is known that TLR4 plays an important role in the development of inflammation and is part of one of the oldest signaling mechanisms of innate immunity [6][7][8], and an important role of TLR7/8 signaling in the development of neuroinflammatory processes has been shown [9,10].…”

“…It is known that monocytes are one of the most sensitive cells of the immune system capable of responding even to minor pathological processes in the body at the earliest stages of the immune response. Therefore, the analysis of the functional status of peripheral blood monocytes can be informative both for assessing the course of the disease and predicting the effectiveness of therapy [1,5,[7][8][9][10][11][12][13]. All this indicates that mononuclear cells are unique and promising object that can be used as a biomarker to predict the course of multiple sclerosis.…”

Genotypic and antigenic study of SARS-CoV-2 from an Indian isolate

“…The TLR adaptor molecules signal through the IKK□/TBK1 complex and the IKKα/IKKβ/IKKγ complex similarly may also involve IRAK-1/IRAK4/TRAF6 complex to activate the transcription factors including IRF3, IRF7, and NF-κBthat ultimately activate IFNs and produces proinflammatory cytokines(Pobezinskaya et al 2008, Ermolaeva MA et al 2008). Previous in vivo study postulates that TLRs signaling programmed by MyD88 adaptor protein and in mice model study reveals the potential involvement of TLR3/TLR4 on SARS-CoV infection(Zheng et al 2020, Perales et al 2013). The study documented that transgenic mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss, mortality, reduced lung function, increased lung pathology, and higher viral titers.…”