Siglec-G Deficiency Ameliorates Hyper-Inflammation and Immune Collapse in Sepsis via Regulating Src Activation.

Abstract

Hyper-inflammation during acute phase and sequential hypo-inflammation during immunosuppressive phase in macrophages/monocytes lead to multiorgan failure syndrome and immune collapse of sepsis, in which toll-like receptor (TLR)-triggered inflammatory responses play a major role. Here, we reported that Siglecg deficiency attenuated TLR4-triggered pro-inflammatory cytokine production and increased anti-inflammatory cytokine [interleukin-10 [IL-10]] production in vivo and in vitro at both acute and immunosuppressive phases. Siglecg deficiency also protected mice from lipopolysaccharide (LPS)-induced sepsis with less inflammation in the lung and less tissue destruction in the spleen. Siglec-G inhibited proto-oncogene tyrosine-protein kinase Src (Src) activation via recruiting and activating tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP1) through immunoreceptor tyrosine-based inhibitory motif (ITIM) domain. Src could inhibit TLR4-induced inflammatory cytokines and promote anti-inflammatory cytokine IL-10. Mechanical investigation showed that Src could interact with and phosphorylate STAT3. Src could also promote HIF1α degradation through activating GSK3β. Our study reveals that Siglec-G orchestrates TLR-induced inflammation, which outlines that blocking Siglec-G or activating Src may be a promising strategy for both acute and chronic inflammatory diseases.

• Authors: Wenqian Li, Yinjiao Li, Kewei Qin, Boxiang Du, Tianliang Li, Hongbin Yuan, Chaofeng Han, Yan Luo
• Journal: Frontiers in immunology (Front Immunol) Vol. 10 Pg. 2575 ( 2019) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 31781099 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Li, Li, Qin, Du, Li, Yuan, Han and Luo.

Chemical References

• Cytokines
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lectins
• NF-kappa B
• Receptors, Antigen, B-Cell
• STAT3 Transcription Factor
• Sialic Acid Binding Immunoglobulin-like Lectins
• Siglecg protein, mouse
• Stat3 protein, mouse
• Toll-Like Receptors
• Interleukin-10
• src-Family Kinases
• SH2 Domain-Containing Protein Tyrosine Phosphatases

Topics

• Animals
• Cytokines (metabolism)
• Enzyme Activation
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Inflammation (immunology)
• Interleukin-10 (metabolism)
• Lectins (deficiency, physiology)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Receptors, Antigen, B-Cell (deficiency, physiology)
• SH2 Domain-Containing Protein Tyrosine Phosphatases (metabolism)
• STAT3 Transcription Factor (metabolism)
• Sepsis (immunology)
• Sialic Acid Binding Immunoglobulin-like Lectins
• Signal Transduction
• Toll-Like Receptors (metabolism)
• src-Family Kinases (metabolism)