Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway.

Abstract

The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps-SHP-2 pathway and control TLR-triggered innate inflammatory responses.

• Authors: Sheng Xu, Xingguang Liu, Yan Bao, Xuhui Zhu, Chaofeng Han, Peng Zhang, Xuemin Zhang, Weihua Li, Xuetao Cao
• Journal: Nature immunology (Nat Immunol) Vol. 13 Issue 6 Pg. 551-9 (Apr 22 2012) ISSN: 1529-2916 [Electronic] United States
• PMID: 22522491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• Interleukin-6
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha
• Interferon-beta
• Proto-Oncogene Proteins c-fes
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Animals
• Escherichia coli (immunology)
• Histocompatibility Antigens Class I (immunology)
• Immunity, Innate (immunology)
• Immunoblotting
• Interferon-beta (immunology)
• Interleukin-6 (immunology)
• Listeria monocytogenes (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (immunology)
• Proto-Oncogene Proteins c-fes (immunology)
• Signal Transduction (immunology)
• Toll-Like Receptors (immunology)
• Tumor Necrosis Factor-alpha (immunology)