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The RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response

Bo Liu1, Jiancheng Huang1, Amina Ashraf1

  • 1Department of Immunology, Sun Yat-sen University, Zhongshan School of Medicine, Guangzhou, Guangdong, China.

Nature Communications
|July 3, 2021
PubMed

Insights

Monocyte chemotactic protein-induced protein 3 (MCPIP3) drives skin inflammation by altering cytokine levels in immune cells. Reducing MCPIP3 protects against inflammatory skin diseases by rebalancing these signals.

Area of Science:

  • Immunology
  • Molecular Biology
  • Dermatology

Background:

  • CCCH zinc finger proteins regulate immune responses by degrading inflammatory cytokine mRNAs.
  • Monocyte chemotactic protein-induced protein 3 (MCPIP3) is a key regulator in this family.
  • MCPIP3 plays a dual role in macrophages and plasmacytoid dendritic cells (pDCs) during inflammation.

Purpose of the Study:

  • To investigate the role of MCPIP3 in skin inflammation, particularly in the context of psoriasis.
  • To elucidate the specific mechanisms by which MCPIP3 influences cytokine production in different immune cell types.
  • To determine the therapeutic potential of targeting MCPIP3 in autoimmune skin conditions.

Main Methods:

  • Analysis of MCPIP3 expression in skin inflammation models.
  • Gene knockout studies in mice to assess MCPIP3 deficiency effects.
  • Measurement of cytokine levels (TNF, IL-6, IL-12p40) in macrophages and pDCs.
  • mRNA degradation assays to identify MCPIP3 targets.

Main Results:

  • MCPIP3 promotes skin inflammation by increasing TNF in macrophages and decreasing IL-6 in pDCs.
  • MCPIP3 deficiency in mice protects against imiquimod-induced psoriasiform lesions.
  • MCPIP3-deficient macrophages produce less TNF and IL-12p40, while pDCs secrete more IL-6.
  • IL-6 from pDCs suppresses macrophage-derived TNF and IL-12p40, indicating a regulatory feedback loop.

Conclusions:

  • MCPIP3 is a critical post-transcriptional regulator that synchronizes myeloid cytokine secretion in autoimmune skin inflammation.
  • MCPIP3 directly degrades mRNAs of IL-6, Regnase-1, and IκBζ, with Regnase-1 feedback degrading MCPIP3 mRNA.
  • Targeting MCPIP3 offers a potential therapeutic strategy for inflammatory skin diseases like psoriasis.

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