Philipp-Alexander Neumann

University of Münster

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Chris Reutelingsperger

Maastricht University

Charles A. Parkos

University of Michigan–Ann Arbor

Dennis H. M. Kusters

University of Michigan–Ann Arbor

Giovanna Leoni

Ludwig-Maximilians-Universität München

James McCoy

Emory University

Mauro Perretti

Queen Mary University of London

Guangjie Cheng

University of Alabama at Birmingham

Andrew S. Neish

Emory University

J. David Lambeth

Emory University

Kousik Kundu

Wellcome Sanger Institute

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Emory University

University of Michigan–Ann Arbor

Maastricht University

Michigan Medicine

AID Atlanta

Georgia Institute of Technology

Maastricht University Medical Centre

University of Geneva

KU Leuven

Ludwig-Maximilians-Universität München

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

Journal of Clinical Investigation (2012)

Giovanna Leoni Ashfaqul Alam Philipp-Alexander Neumann J. David Lambeth Guangjie Cheng

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.

NOX1

Annexin A1

Formyl peptide receptor

Intestinal mucosa

Intestinal epithelium

10.1172/jci65831

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