Format

Send to

Choose Destination
Blood. 2014 Dec 4;124(24):3515-23. doi: 10.1182/blood-2014-01-552943. Epub 2014 Oct 2.

Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin α3β1-dependent.

Author information

1
David H. Smith Center for Vaccine Biology and Immunology, Department of Pharmacology and Physiology.
2
David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology.
3
Pulmonary and Critical Care Medicine Division, and.
4
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY; and.
5
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
6
David H. Smith Center for Vaccine Biology and Immunology, Department of Pharmacology and Physiology, Department of Microbiology and Immunology.

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.

PMID:
25278585
PMCID:
PMC4256905
DOI:
10.1182/blood-2014-01-552943
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center