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

JCI Insight. 2022 Aug 22;7(16):e156255. doi: 10.1172/jci.insight.156255.

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.

Keywords: Bacterial infections; Infectious disease; Innate immunity; Tight junctions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Disease Models, Animal
  • Immunoglobulin A
  • Junctional Adhesion Molecule A*
  • Mice
  • Mice, Inbred C57BL
  • Phagocytosis
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Sepsis* / genetics

Substances

  • Cell Adhesion Molecules
  • F11r protein, mouse
  • Immunoglobulin A
  • Junctional Adhesion Molecule A
  • Receptors, Cell Surface