Targeting ADAM17 in leukocytes increases neutrophil recruitment and reduces bacterial spread during polymicrobial sepsis

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13 Scopus citations

Abstract

A rapid and robust recruitment of circulating neutrophils at sites of infection is critical for preventing bacterial spread. The efficiency of this process, however, is greatly diminished during sepsis, a severe systemic inflammatory response to infection. The proteolytic activity of a disintegrin and metalloprotease-17 is induced in the cell membrane of leukocytes upon their activation, resulting in the conversion of membrane to soluble TNF-α and the release of assorted receptors from the surface of neutrophils important for their effector functions. We show that conditional knockout mice lacking a disintegrin and metalloprotease-17 in all leukocytes had a survival advantage when subjected to polymicrobial sepsis. Bacteremia and the levels of circulating proinflammatory cytokines, key determinants of sepsis severity, were significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice during sepsis. Although cecal bacterial microbiota and load were similar in unmanipulated conditional a disintegrin and metalloprotease-17 knockout and control mice, peritoneal spread of bacteria was significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice following sepsis induction, which was associated with an amplified recruitment of neutrophils. Taken together, our findings suggest that extensive a disintegrin and metalloprotease-17 induction during sepsis may tip the balance between efficient and impaired neutrophil recruitment.

Original languageEnglish (US)
Pages (from-to)999-1004
Number of pages6
JournalJournal of Leukocyte Biology
Volume100
Issue number5
DOIs
StatePublished - Nov 2016

Bibliographical note

Funding Information:
This study was supported by Grants AI103328, AI107543, and HL128580 (to B.W.) from the U.S. National Institutes of Health.

Publisher Copyright:
© Society for Leukocyte Biology.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • Inflammation
  • Microbiota
  • TACE

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