Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair
2013
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 biologyin 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 adhesionkinase (FAK) and
paxillin. In vivo studies using intestinal epithelial specific
Nox1–/–IEC and AnxA1–/– mice demonstrated defects in intestinal mucosal wound repair, while
systemic administrationof ANXA1 promoted wound recovery in a
NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the
intestinal epitheliumand 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.
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