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.
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Leoni
authors.forename: Ashfaqul
authors.initials: A
authors.lastname: Alam
authors.forename: Philipp-Alexander
authors.initials: PA
authors.lastname: Neumann
authors.forename: J David
authors.initials: JD
authors.lastname: Lambeth
authors.forename: Guangjie
authors.initials: G
authors.lastname: Cheng
authors.forename: James
authors.initials: J
authors.lastname: McCoy
authors.forename: Roland S
authors.initials: RS
authors.lastname: Hilgarth
authors.forename: Kousik
authors.initials: K
authors.lastname: Kundu
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.forename: Dennis
authors.initials: D
authors.lastname: Kusters
authors.forename: Chris
authors.initials: C
authors.lastname: Reutelingsperger
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Neish
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D017305:Annexin A1; D010455:Peptides; D017382:Reactive Oxygen Species; C096153:annexin A1 peptide (2-26); C573274:annexin A1, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C000614711:NOX1 protein, mouse; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse