Inhibition of Efferocytosis by Extracellular CIRP-Induced Neutrophil Extracellular Traps.

Abstract

Phagocytic clearance of apoptotic cells by the macrophages (efferocytosis) is impaired in sepsis, but its mechanism is poorly understood. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel damage-associated molecular pattern that fuels inflammation. We identify that eCIRP-induced neutrophil extracellular traps (NETs) impair efferocytosis through a novel mechanism. Coculture of macrophages and apoptotic thymocytes in the presence of recombinant murine CIRP (rmCIRP)-induced NETs significantly inhibited efferocytosis. Efferocytosis was significantly inhibited in the presence of rmCIRP-treated wild-type (WT), but not PAD4-/- neutrophils. Efferocytosis in the peritoneal cavity of rmCIRP-injected PAD4-/- mice was higher than WT mice. Milk fat globule-EGF-factor VIII (MFG-E8), an opsonin, increased macrophage efferocytosis, whereas the inhibition of efferocytosis by NETs was not rescued upon addition of MFG-E8, indicating disruption of MFG-E8's receptor(s) αvβ3 or αvβ5 integrin by the NETs. We identified neutrophil elastase in the NETs significantly inhibited efferocytosis by cleaving macrophage surface integrins αvβ3 and αvβ5 Using a preclinical model of sepsis, we found that CIRP-/- mice exhibited significantly increased rate of efferocytosis in the peritoneal cavity compared with WT mice. We discovered a novel role of eCIRP-induced NETs to inhibit efferocytosis by the neutrophil elastase-dependent decrease of αvβ3/αvβ5 integrins in macrophages. Targeting eCIRP ameliorates sepsis by enhancing efferocytosis.

• Authors: Kehong Chen, Atsushi Murao, Adnan Arif, Satoshi Takizawa, Hui Jin, Jianxin Jiang, Monowar Aziz, Ping Wang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 206 Issue 4 Pg. 797-806 (02 15 2021) ISSN: 1550-6606 [Electronic] United States
• PMID: 33380498 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by The American Association of Immunologists, Inc.

Chemical References

• Cirbp protein, mouse
• RNA-Binding Proteins

Topics

• Animals
• Coculture Techniques
• Extracellular Traps (genetics, immunology)
• Macrophages (immunology)
• Male
• Mice
• Mice, Knockout
• Neutrophils (immunology)
• RNA-Binding Proteins (genetics, immunology)
• Sepsis (genetics, immunology)
• Thymocytes (immunology)