The RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response

Bo Liu, Jiancheng Huang, Amina Ashraf, Oindrila Rahaman, Jing Lou, Ling Wang, Peiliang Cai, Jinping Wen, Shoaib Anwaar, Xiaoli Liu, Hai Ni, Dipyaman Ganguly, Jijun Zhao () and Cliff Y. Yang ()
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Bo Liu: Zhongshan School of Medicine, Guangzhou
Jiancheng Huang: Zhongshan School of Medicine, Guangzhou
Amina Ashraf: Zhongshan School of Medicine, Guangzhou
Oindrila Rahaman: CSIR-Indian Institute of Chemical Biology
Jing Lou: Zhongshan School of Medicine, Guangzhou
Ling Wang: Zhongshan School of Medicine, Guangzhou
Peiliang Cai: Zhongshan School of Medicine, Guangzhou
Jinping Wen: Zhongshan School of Medicine, Guangzhou
Shoaib Anwaar: Zhongshan School of Medicine, Guangzhou
Xiaoli Liu: Zhongshan School of Medicine, Guangzhou
Hai Ni: Zhongshan School of Medicine, Guangzhou
Dipyaman Ganguly: CSIR-Indian Institute of Chemical Biology
Jijun Zhao: Sun Yat-sen University
Cliff Y. Yang: Zhongshan School of Medicine, Guangzhou

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract CCCH zinc finger proteins resolve immune responses by degrading the mRNAs of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Here we report that one such family member, monocyte chemotactic protein-induced protein 3 (MCPIP3, also named ZC3H12C or Regnase-3), promotes skin inflammation by simultaneously enhancing TNF in macrophages and repressing IL-6 in plasmacytoid dendritic cells (pDCs). MCPIP3 is positively associated with psoriasis pathogenesis, and highly expressed by macrophages and pDCs. MCPIP3-deficient macrophages produce less TNF and IL-12p40. However, MCPIP3-deficient pDCs secrete significantly more IL-6. This enhanced intradermal IL-6 may alleviate imiquimod-induced skin inflammation. As a result, MCPIP3-deficient mice are protected from imiquimod-induced psoriasiform lesions. Furthermore, early exposure to pDC-derived IL-6 suppresses macrophage-derived TNF and IL-12p40. Mechanistically, MCPIP3 could directly degrade mRNAs of IL-6, Regnase-1, and IκBζ. In turn, Regnase-1 could degrade MCPIP3 mRNAs. Our study identifies a critical post-transcriptional mechanism that synchronizes myeloid cytokine secretion to initiate autoimmune skin inflammation.

Date: 2021
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DOI: 10.1038/s41467-021-24352-w

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