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Tetraspan MS4A6D is a coreceptor of MHC class II antigen (MHC-II) that promotes macrophages-derived inflammation

Yue Chen1, Sirui Li2, Xiaoyong Huang2

  • 1Institute of Medicine, Southwest University, Chongqing 400033, China.

Molecular Immunology
|July 10, 2023
PubMed

Insights

Tetraspan MS4A6D adapter regulates NLRP3 inflammasome activation. Inhibiting MS4A6D homodimerization or Tyr241 phosphorylation protects against endotoxin lethality, offering a therapeutic target for inflammatory disorders.

Area of Science:

  • Immunology
  • Molecular Biology

Background:

  • The tetraspan MS4A6D protein acts as a VSIG4 adapter, influencing NLRP3 inflammasome activation.
  • The precise expression, distribution, and biological functions of MS4A6D remain incompletely understood.

Purpose of the Study:

  • To elucidate the expression patterns, regulatory mechanisms, and functional role of MS4A6D in innate immunity and inflammation.

Main Methods:

  • Utilized Ms4a6d-deficient mice and macrophage cell models.
  • Investigated MS4A6D expression, NKX2-1 regulation, and its interaction with MHC-II.
  • Analyzed signaling pathways including SYK-CREB and downstream inflammatory gene expression.
  • Assessed the impact of MS4A6D mutations (C237G, Y241G) on inflammatory responses and survival.

Main Results:

  • MS4A6D is predominantly expressed in mononuclear phagocytes, with its gene transcription regulated by NKX2-1.
  • Ms4a6d-deficient mice exhibited enhanced survival against lipopolysaccharide challenge.
  • MS4A6D forms homodimers with MHC-II, leading to Tyr241 phosphorylation and activation of SYK-CREB signaling.
  • This cascade augments pro-inflammatory gene transcription (Il1b, Il6, Tnfa) and mitochondrial ROS secretion.
  • Specific mutations disrupting MS4A6D homodimerization or Tyr241 phosphorylation conferred protection against endotoxin-induced lethality.

Conclusions:

  • MS4A6D plays a critical role in amplifying inflammatory responses by forming a signaling complex with MHC-II.
  • Targeting MS4A6D-mediated signaling offers a potential therapeutic strategy for managing macrophage-associated inflammatory conditions.
Keywords:
CREBMHC-IIMS4A6DMacrophagesSYK

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