Neutrophil interactions with apical epithelial ICAM‐1 contribute to resolution of inflammation by promoting intestinal epithelial wound repair.

Abstract

A prominent feature of neutrophil (PMN) infiltration of the intestinal mucosa is transepithelial migration (TEM) that is associated with epithelial injury, barrier dysfunction and disease symptoms. While PMN TEM has been extensively characterized, the functional significance of PMN interactions with the luminal (apical) epithelial surface on intestinal epithelial cell (IEC) homeostasis is not clear. Here we show that under inflammatory conditions, PMN adhesion to upregulated ICAM‐1 on the apical epithelial membrane may initiate wound repair through increased cell proliferation. Specifically, we report that PMN adhesion to IEC ICAM‐1 results in activation of Akt and β‐catenin pathways leading to nuclear translocation of β‐catenin, and initiation of proliferative responses, as determined by incorporation of Edu. Such responses were ICAM‐1 dependent, as experiments modeling neutrophil engagement of epithelial ICAM‐1 by antibody‐mediated crosslinking yielded similar results. Furthermore, antibody‐crosslinking of ICAM‐1 enhanced epithelial wound repair in scratch wound assays. These findings suggest that while acute PMN TEM results in epithelial wounds, subsequent upregulation and engagement of ICAM‐1 by PMN on the luminal surface may mediate reparative proliferative responses.