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FASEB J. 2019 Dec;33(12):13660-13668. doi: 10.1096/fj.201901231R. Epub 2019 Oct 8.

The olfactomedin-4 positive neutrophil has a role in murine intestinal ischemia/reperfusion injury.

Author information

1
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
2
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
3
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Abstract

Olfactomedin-4 (OLFM4) identifies a subset of neutrophils conserved in both mouse and man, associated with worse outcomes in several inflammatory conditions. We investigated the role of OLFM4-positive neutrophils in murine intestinal ischemia/reperfusion (IR) injury. Wild-type (WT) C57Bl/6 and OLFM4 null mice were subjected to intestinal IR injury and then monitored for survival or tissues harvested for further analyses. In vivo intestinal barrier function was determined via functional assay of permeability to FITC-dextran. OLFM4 null mice had a significant 7-d survival benefit and less intestinal barrier dysfunction compared with WT. Early after IR, WT mice had worse mucosal damage on histologic examination. Experiments involving adoptive transfer of bone marrow demonstrated that the mortality phenotype associated with OLFM4-positive neutrophils was transferrable to OLFM4 null mice. After IR injury, WT mice also had increased intestinal tissue activation of NFκB and expression of iNOS, 2 signaling pathways previously demonstrated to be involved in intestinal IR injury. In combination, these experiments show that OLFM4-positive neutrophils are centrally involved in the pathologic pathway leading to intestinal damage and mortality after IR injury. This may provide a therapeutic target for mitigation of intestinal IR injury in a variety of common clinical situations.-Levinsky, N. C., Mallela, J., Opoka, A., Harmon, K., Lewis, H. V., Zingarelli, B., Wong, H. R., Alder, M. N. The olfactomedin-4 positive neutrophil has a role in murine intestinal ischemia/reperfusion injury.

KEYWORDS:

OLFM4; iNos; neutrophil heterogeneity; neutrophil subsets

PMID:
31593636
DOI:
10.1096/fj.201901231R

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