Toll-Like Receptor 4-Myeloid Differentiation Primary Response Gene 88 Pathway Is Involved in the Inflammatory Development of Polymyositis by Mediating Interferon-γ and Interleukin-17A in Humans and Experimental Autoimmune Myositis Mouse Model.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Hongya Zhang, Fangyuan He, Ming Shi, Wenxiu Wang, Xiaojia Tian, Juan Kang, Wenjuan Han, Rui Wu, Linfu Zhou, Mengmeng Hu, Xiaobo Li, Fang Mi, Gang Zhao, Hongge Jia
• Journal: Frontiers in neurology (Front Neurol) Vol. 8 Pg. 132 ( 2017) ISSN: 1664-2295 [Print] Switzerland
• PMID: 28446897 (Publication Type: Journal Article)