Title
Extracellular CIRP and TREM-1 axis promotes ICAM-1-Rho-mediated NETosis in sepsis
Publication Date
2020
Journal Title
FASEB J
Abstract
© 2020 Federation of American Societies for Experimental Biology Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern (DAMP). Intercellular adhesion molecule-1 (ICAM-1) expressing neutrophils produce excessive amounts of neutrophil extracellular traps (NETs). We reveal that eCIRP generates ICAM-1+ neutrophils through triggering receptor expressed on myeloid cells-1 (TREM-1) and the ICAM-1+ neutrophils involve Rho GTPase to promote NETosis. Treatment of BMDN with rmCIRP increased the frequency of ICAM-1+ BMDN, while rmCIRP-treated TREM-1−/− BMDN or pretreatment of BMDN with TREM-1 inhibitor LP17 significantly decreased the frequency of ICAM-1+ neutrophils. The frequencies of ICAM-1+ neutrophils in blood and lungs were markedly decreased in rmCIRP-injected mice or septic mice treated with LP17. Coculture of ICAM-1−/− neutrophils or wild-type (WT) neutrophils with WT macrophages in the presence of a peptidylarginine deiminase 4 (PAD4) inhibitor reduced TNF-α and IL-6 compared to WT neutrophils treated with rmCIRP. Treatment of ICAM-1−/− neutrophils with rmCIRP resulted in reduced quantities of NETs compared to WT rmCIRP-treated neutrophils. Treatment of BMDN with rmCIRP-induced Rho activation, while blockade of ICAM-1 significantly decreased Rho activation. Inhibition of Rho significantly decreased rmCIRP-induced NET formation in BMDN. TREM-1 plays a critical role in the eCIRP-mediated increase of ICAM-1 expression in neutrophils, leading to the increased NET formation via Rho activation to exaggerate inflammation.
Volume Number
34
Issue Number
7
Pages
9771-9786
Document Type
Article
Status
Faculty; Northwell Researcher; Northwell Resident
Facility
School of Medicine; Northwell Health
Primary Department
Molecular Medicine
PMID
DOI
10.1096/fj.202000482R