Neutrophil (PMN) infiltration of the intestinal mucosa often leads to severe epithelial injury; however, how this process occurs is unclear. This article describes a novel mechanism whereby membrane-derived microparticles released by tissue infiltrating PMNs (PMN-MPs) serve as shuttles to protect and deliver active mediators to locally modulate cellular function during inflammation. Specifically, myeloperoxidase (MPO), which is abundantly expressed in PMN azurophilic granules and is used for microbial killing, was found to be mobilized to the PMN surface and subsequently released in association with PMN-MPs upon PMN activation and binding to intestinal epithelial cells (IECs). The enzymatic activity of PMN-MP–associated MPO was enhanced compared with soluble protein, leading to potent inhibition of wound closure following PMN-MP binding to IECs. Importantly, localized microinjection of PMN-MPs into wounded colonic mucosa was sufficient to impair epithelial wound healing in vivo. PMN-MP/MPO–dependent inhibition of IEC wound healing was due to impaired IEC migration and proliferation, resulting from impeded actin dynamics, cell spreading, and cell cycle arrest. Thus, our findings provide new insight into mechanisms governing PMN-induced tissue injury and implicate PMN-MPs and MPO as important regulators of cellular function.
This work was supported by grants from the National Institutes of Health (DK101675) and the American Cancer Society (IRG-9303718).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- annexin A1
- coxsackievirus and adenovirus receptor
- HBSS containing calcuim and magnesium
- inflammatory bowel disease
- intestinal epithelial cell
- junctional adhesion molecule–like protein
- latrunculin B
- matrix metalloproteinase
- microparticle released by tissue-infiltrating PMN
- reactive oxygen species
- Received October 24, 2016.
- Accepted January 29, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.