title: Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin α3β1-dependent.
abstract: Integrin-mediated migration of neutrophils to infected tissue sites is vital for pathogen clearance and therefore host survival. Although β2 integrins have been shown to mediate neutrophil transendothelial migration during systemic and local inflammation, relatively little information is available regarding neutrophil migration in sepsis beyond the endothelial cell layer. In this study, we report that integrin α3β1 (VLA-3; CD49c/CD29) is dramatically upregulated on neutrophils isolated from both human septic patients and in mouse models of sepsis. Compared with the α3β1 (low) granulocytes, α3β1 (high) cells from septic animals displayed hyperinflammatory phenotypes. Administration of a α3β1 blocking peptide and conditional deletion of α3 in granulocytes significantly reduced the number of extravasating neutrophils and improved survival in septic mice. In addition, expression of α3β1 on neutrophils was associated with Toll-like receptor-induced inflammatory responses and cytokine productions. Thus, our results show that α3β1 is a novel marker of tissue homing and hyperresponsive neutrophil subtypes in sepsis, and blocking of α3β1 may represent a new therapeutic approach in sepsis treatment.
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, Department of Pharmacology and Physiology.
authors.forename: Yelena V
authors.initials: YV
authors.lastname: Lerman
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology.
authors.forename: Kihong
authors.initials: K
authors.lastname: Lim
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Hyun
authors.affiliation: Pulmonary and Critical Care Medicine Division, and.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Falkner
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY; and.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Pulmonary and Critical Care Medicine Division, and.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Pietropaoli
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology.
authors.forename: Pranita P
authors.initials: PP
authors.lastname: Sarangi
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, Department of Pharmacology and Physiology, Department of Microbiology and Immunology.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D039201:Integrin alpha3beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D039201:Integrin alpha3beta1; D010455:Peptides; D051193:Toll-Like Receptors