Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis
Nathan J. Klingensmith, Katherine T. Fay, David A. Swift, Julia M.R. Bazzano, John D. Lyons, Ching-wen Chen, Mei Meng, Kimberly M. Ramonell, Zhe Liang, Eileen M. Burd, Charles A. Parkos, Mandy L. Ford, Craig M. Coopersmith
Nathan J. Klingensmith, Katherine T. Fay, David A. Swift, Julia M.R. Bazzano, John D. Lyons, Ching-wen Chen, Mei Meng, Kimberly M. Ramonell, Zhe Liang, Eileen M. Burd, Charles A. Parkos, Mandy L. Ford, Craig M. Coopersmith
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Research Article Infectious disease

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

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.

Authors

Nathan J. Klingensmith, Katherine T. Fay, David A. Swift, Julia M.R. Bazzano, John D. Lyons, Ching-wen Chen, Mei Meng, Kimberly M. Ramonell, Zhe Liang, Eileen M. Burd, Charles A. Parkos, Mandy L. Ford, Craig M. Coopersmith

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Figure 2

Bacteremia, cytokines, and survival in septic JAM-A–/– mice.

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Bacteremia, cytokines, and survival in septic JAM-A–/– mice. (A) Despite...
(A) Despite intestinal hyperpermeability, bacteremia was lower in JAM-A–/– mice (P = 0.004; n = 18 WT, n = 20 JAM-A–/–); 75% of animals had no bacterial growth. (B–E) Serum levels of pro-inflammatory cytokines TNF (P = 0.01; n = 10 WT, n = 10 JAM-A–/–) and IL-1β (P = 0.03; n = 10 WT, n = 10 JAM-A–/–) were lower in septic JAM-A–/– mice than in WT mice, whereas there were no differences in either IL-6 (P = 0.75; n = 10 WT, n = 10 JAM-A–/–) or IL-10 (P = 0.22; n = 9 WT, n = 9 JAM-A–/–) levels. (F) Body temperature was lower in septic JAM-A–/– mice in the first 3 hours after sepsis. However, body temperature rapidly recovered in KO mice, whereas WT mice progressed to worsening hypothermia, which did not recover by 24 hours (P < 0.05 at 2, 3, 8, 9, 10, 11, and 24 hours; P > 0.05 at baseline and at 1, 4, 5, 6, and 7 hours; n = 5 WT, n = 7 JAM-A–/– for each time point). (G) Survival rate was significantly higher in septic JAM-A–/– mice (P = 0.003; n = 20 WT, n = 20 JAM-A–/–). (H) Survival was similar in mice with enterocyte-specific JAM-A deletion and WT mice (P = 0.28; n = 20 WT, n = 14 JAM-A–/–). (A–F) Data were subjected to a 1-tailed t testand the Mann-Whitney U test depending on presence of Gaussian distribution. (G and H) Log-rank test was applied to the data. *P < 0.05, **P < 0.01.