Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals.

Xia-Ping Yao, Jian Ye, Ting Feng, Feng-Chao Jiang, Ping Zhou, Fang Wang, Jian-Guo Chen, Peng-Fei Wu

Brain, behavior, and immunity 2023 Feb

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Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called 'myddosome', was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Xia-Ping Yao, Jian Ye, Ting Feng, Feng-Chao Jiang, Ping Zhou, Fang Wang, Jian-Guo Chen, Peng-Fei Wu. Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals. Brain, behavior, and immunity. 2023 Feb;108:204-220