Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation.

Yaoyao Xia, Qingzhuo Zhang, Yuyi Ye, Xiaoyan Wu, Fang He, Yuanyi Peng, Yulong Yin, Wenkai Ren

Clinical and translational medicine 2022 Feb

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Immunotransmitters (e.g., neurotransmitters and neuromodulators) could orchestrate diverse immune responses; however, the elaborated mechanism by which melatonergic activation governs inflammation remains less defined. Primary macrophages, various cell lines, and Pasteurella multocida (PmCQ2)-infected mice were respectively used to illustrate the influence of melatonergic signalling on inflammation in vitro and in vivo. A series of methods (e.g., RNA-seq, metabolomics, and genetic manipulation) were conducted to reveal the mechanism whereby melatonergic signalling reduces macrophage inflammation. Here, we demonstrate that melatonergic activation substantially lessens interleukin (IL)-1β-dependent inflammation. Treatment of macrophages with melatonin rewires metabolic program, as well as remodels signalling pathways which depends on interferon regulatory factor (IRF) 7. Mechanistically, melatonin acts via membrane receptor (MT) 1 to increase heat shock factor (Hsf) 1 expression through lowering the inactive glycogen synthase kinase (GSK3) β, thereby transcriptionally inhibiting interferon (IFN)-γ receptor (IFNGR) 2 and ultimately causing defective canonical signalling events [Janus kinase (JAK) 1/2-signal transducer and activator of transcription (STAT) 1-IRF7] and lower IL-1β production in macrophages. Moreover, we find that melatonin amplifies host protective responses to PmCQ2 infection-induced pneumonia. Our conceptual framework provides potential therapeutic targets to prevent and/or treat inflammatory diseases associating with excessive IL-1β production. © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Citation

Yaoyao Xia, Qingzhuo Zhang, Yuyi Ye, Xiaoyan Wu, Fang He, Yuanyi Peng, Yulong Yin, Wenkai Ren. Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation. Clinical and translational medicine. 2022 Feb;12(2):e716