Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair
Giovanna Leoni, … , Andrew S. Neish, Asma Nusrat
Giovanna Leoni, … , Andrew S. Neish, Asma Nusrat
Published December 17, 2012
Citation Information: J Clin Invest. 2013;123(1):443-454. https://doi.org/10.1172/JCI65831.
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Research Article Gastroenterology

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

Abstract

N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1–/–IEC and AnxA1–/– mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.

Authors

Giovanna Leoni, Ashfaqul Alam, Philipp-Alexander Neumann, J. David Lambeth, Guangjie Cheng, James McCoy, Roland S. Hilgarth, Kousik Kundu, Niren Murthy, Dennis Kusters, Chris Reutelingsperger, Mauro Perretti, Charles A. Parkos, Andrew S. Neish, Asma Nusrat

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Figure 5

ANXA1 accelerates in vivo intestinal mucosal wound healing and recovery via NOX1.

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ANXA1 accelerates in vivo intestinal mucosal wound healing and recovery ...
(A) Endoscopic images of healing colonic mucosal wounds 2 or 4 days after biopsy-induced injury in WT and Nox1–/–IEC mice treated with i.p. injections of PBS or ANXA1 (5 μg, twice/day). Quantification of wound repair is shown in the graph. ANXA1 administration promoted recovery of wounds in WT mice, but in the absence of NOX1 resulted in a significant delay in wound healing. (B) Clinical disease activity index (DAI) of mice subjected to DSS colitis for 7 days, followed by recovery from colitis for 6 days. ANXA1 was administered i.p. (5 μg, twice/day) during recovery. Significantly decreased DAI was observed in WT mice treated with ANXA1 (red line) compared with control mice treated with PBS (black line). However, ANXA1 failed to enhance recovery in Nox1–/–IEC mice (blue line). (C) Representative photomicrographs of H&E-stained histological sections. Boxed areas are magnified in insets. The total magnification of the photomicrographs is ×2 and in the insets it is ×40. Data in all graphs are presented as mean ± SEM; *P < 0.05 and **P < 0.001, WT ANXA1 vs. WT PBS, n = 12 mice/group; #P < 0.05 and ##P < 0.01, Nox1–/–IEC ANXA1 vs. Nox1–/–IEC PBS, n = 12 mice/group.