title: Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome.
abstract: Cold-inducible RNA-binding protein (CIRP) is a damage-associated molecular pattern (DAMP) molecule which stimulates proinflammatory cytokine release in hemorrhage and sepsis. Under these medical conditions, disruption of endothelial homeostasis and barrier integrity, typically induced by proinflammatory cytokines, is an important factor contributing to morbidity and mortality. However, the role of CIRP in causing endothelial dysfunction has not been investigated. In this study, we show that intravenous injection of recombinant murine CIRP (rmCIRP) in C57BL/6 mice causes lung injury, evidenced by vascular leakage, edema, increased leukocyte infiltration and cytokine production in the lung tissue. The CIRP-induced lung damage is accompanied with endothelial cell (EC) activation marked by upregulation of cell-surface adhesion molecules E-selectin and ICAM-1. Using in vitro primary mouse lung vascular ECs (MLVECs), we demonstrate that rmCIRP treatment directly increases the ICAM-1 protein expression and activates NAD(P)H oxidase in MLVECs. Importantly, CIRP stimulates the assembly and activation of Nlrp3 inflammasome in MLVECs accompanied with caspase-1 activation, IL-1β release and induction of proinflammatory cell death pyroptosis. Finally, our study demonstrates CIRP-induced EC pyroptosis in the lungs of C57BL/6 mice for the first time. Taken together, the released CIRP in shock can directly activate ECs and induce EC pyroptosis to cause lung injury.
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY, USA.
authors.forename: Weng-Lang
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Archna
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004727:Endothelium / Q000276:immunology / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D000069292:Pyroptosis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C106176:Cirbp protein, mouse; D016207:Cytokines; D019040:E-Selectin; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016601:RNA-Binding Proteins; C546936:SELE protein, human; D018799:Intercellular Adhesion Molecule-1; D020170:Caspase 1