The RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response

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 I kappa B zeta. 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. Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.

Automated summary

MCPIP3, a CCCH zinc finger protein, plays a key role in promoting skin inflammation by manipulating cytokine profiles in pDCs and macrophages. MCPIP3 deficiency alters immune responses, leading to protection against Imiquimod-induced psoriasiform lesions in mice. The study highlights the critical role of post-transcriptional mechanisms in coordinating myeloid cytokine secretion during autoimmune skin inflammation.