Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis

• Type of Material: Article
• Authors: Nathan Klingensmith, Emory University; Katherine Fay, Emory University; David A Swift, Emory University; Julia M Bazzano, Emory University; John Lyons, Emory University; Ching-Wen Chen, Emory University; Mei Meng, Emory University; Kimberly M Ramonell, Emory University; Zhe Liang, Emory University; Eileen Burd, Emory University; Charles A Parkos, University of Michigan; Mandy Ford, Emory University; Craig Coopersmith, Emory University
• Language: English
• Date: 2022-08-22
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Klingensmith et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.156255
• Title of Journal or Parent Work: JCI INSIGHT
• Volume: 7
• Issue: 16
• Grant/Funding Information: This work was supported by funding from the NIH (grants GM072808, GM095442, GM104323, AA027396, AI149274, DK72564, and DK61379).
• Keywords: JAM-A; Research & Experimental Medicine; MUCOSAL BARRIER; CELLS; Life Sciences & Biomedicine; EPITHELIAL APOPTOSIS; Medicine, Research & Experimental; PROTECTION; Science & Technology; SEPTIC SHOCK; TIGHT JUNCTIONS; MICROBIOME; MECHANISMS; DYSFUNCTION
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Expression of the tight junction-associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A -/- mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1β expression. Survival is improved in JAM-A-/- mice. However, intestine-specific JAM-A-/- deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- × RAG-/- mice have improved survival compared with RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A-/- mice, while septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.