title: Neutrophil-derived JAML inhibits repair of intestinal epithelial injury during acute inflammation.
abstract: Neutrophil transepithelial migration (TEM) during acute inflammation is associated with mucosal injury. Using models of acute mucosal injury in vitro and in vivo, we describe a new mechanism by which neutrophils infiltrating the intestinal mucosa disrupt epithelial homeostasis. We report that junctional adhesion molecule-like protein (JAML) is cleaved from neutrophil surface by zinc metalloproteases during TEM. Neutrophil-derived soluble JAML binds to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) resulting in compromised barrier and inhibition of wound repair, through decreased epithelial proliferation. The deleterious effects of JAML on barrier and wound repair are reversed with an anti-JAML monoclonal antibody that inhibits JAML-CAR binding. JAML released from transmigrating neutrophils across inflamed epithelia may thus promote recruitment of leukocytes and aid in clearance of invading microorganisms. However, sustained release of JAML under pathologic conditions associated with persistence of large numbers of infiltrated neutrophils would compromise intestinal barrier and inhibit mucosal healing. Thus, targeting JAML-CAR interactions may improve mucosal healing responses under conditions of dysregulated neutrophil recruitment.
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Weber
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sumagin
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: I C
authors.initials: IC
authors.lastname: McCall
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: G
authors.initials: G
authors.lastname: Leoni
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Neumann
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: R
authors.initials: R
authors.lastname: Andargachew
authors.affiliation: 1] Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA [2] Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Brazil
authors.affiliation: 1] Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA [2] Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: O
authors.initials: O
authors.lastname: Medina-Contreras
authors.affiliation: 1] Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA [2] Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Denning
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nusrat
authors.affiliation: 1] Epithelial Pathobiology and Mucosal Inflammation Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA [2] Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Parkos
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism; D003412:Cricetulus; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D007410:Intestinal Diseases / Q000276:immunology / Q000503:physiopathology*; D018448:Models, Immunological; D009504:Neutrophils / Q000276:immunology*; D011485:Protein Binding; D014945:Wound Healing / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; C479820:JAML protein, human