Abstract
Toll-like receptor 4 (TLR4) is one of the key players in the development of many autoimmune diseases. To determine the possible role of TLR4 in polymyositis (PM) development, we collected muscle samples from PM patients and mice subjected to an experimental autoimmune myositis (EAM) model. We measured TLR4-MyD88 pathway-related factors, interferon-γ (IFN-γ), and interleukin-17A (IL-17A) in EAM mice and PM patients. Then, we observed the changes of above factors and the inflammatory development of EAM mice with TLR4 antagonist TAK-242, IFN-γ, or IL-17A antibody treatment. The expression of TLR4, MyD88, and NF-κB was significantly upregulated in the muscle tissues both in 22 patients with PM and in the EAM model. As expected, increased levels of various cytokines, such as IL-1β, IL-6, IL-10, IL-12, tumor necrosis factor-α, TGF-β, IFN-γ, and IL-17A, were evident in the serum of EAM mice. Moreover, mRNA expression levels of IFN-γ and IL-17A were significantly increased in both PM patients and EAM mice. Consistently, the levels of these factors were positively correlated with the degree of muscle inflammation in EAM mice. However, when EAM mice were treated with TLR4 antagonist TAK-242, the expression of IFN-γ and IL-17A was decreased. When the cytokines were neutralized by anti-IFN-γ or anti-IL-17A antibody, the inflammatory development of EAM exacerbated or mitigated. The present study provided the important evidence that the TLR4-MyD88 pathway may be involved in the immune mechanisms of PM by mediating IFN-γ and IL-17A.
Highlights
Polymyositis (PM) is a major clinical subtype of the idiopathic inflammatory myopathies, which is classified as an autoimmune disease [1,2,3,4] and still lacks effective therapy
Our data from PM patients showed elevated levels of serum erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase (LDH), alanine transaminase (ALT), and aspartate transaminase (AST), some of which were over 10 times the normal ceiling value (Table 1)
PM is often diagnosed by clinical symptoms, kinase examination, and muscle biopsy, more and more studies indicated that autoantibodies existed in the PM patients [5, 29, 30]
Summary
Polymyositis (PM) is a major clinical subtype of the idiopathic inflammatory myopathies, which is classified as an autoimmune disease [1,2,3,4] and still lacks effective therapy. Females are affected more often than males at a ratio of approximately 2:1. The clinical symptoms are characterized by acute or subacute progressive muscle weakness, endomysia inflammatory cell infiltration, creatine kinase elevation, and abnormal electromyogram (EMG) [6]. PM is histologically characterized by the presence of endomysial inflammatory infiltrates consisting of CD8+ T cells invading non-necrotic muscle fibers that express major histocompatibility complex class I (MHC-I) molecules on the sarcolemma [7]. CD8/MHC-I complex has become a characteristic diagnostic tool for PM. The mechanisms underlying PM pathological process are still largely unknown
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