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

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

doi:10.1172/JCI65831

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

198 Citations (Web of Science)

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.

Original language	English
Pages (from-to)	443-454
Journal	Journal of Clinical Investigation
Volume	123
Issue number	1
DOIs	https://doi.org/10.1172/JCI65831
Publication status	Published - Jan 2013

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10.1172/JCI65831

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Leoni, G., Alam, A., Neumann, P-A., Lambeth, J. D., Cheng, G., McCoy, J., Hilgarth, R. S., Kundu, K., Murthy, N., Kusters, D., Reutelingsperger, C., Perretti, M., Parkos, C. A., Neish, A. S., & Nusrat, A. (2013). Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. Journal of Clinical Investigation, 123(1), 443-454. https://doi.org/10.1172/JCI65831

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title = "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.",

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

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T1 - Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

AU - Leoni, Giovanna

AU - Alam, Ashfaqul

AU - Neumann, Philipp-Alexander

AU - Lambeth, J. David

AU - Cheng, Guangjie

AU - McCoy, James

AU - Hilgarth, Roland S.

AU - Kundu, Kousik

AU - Murthy, Niren

AU - Kusters, Dennis

AU - Reutelingsperger, Chris

AU - Perretti, Mauro

AU - Parkos, Charles A.

AU - Neish, Andrew S.

AU - Nusrat, Asma

PY - 2013/1

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N2 - 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.

AB - 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.

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