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 4

B cells and immunoglobulins in septic JAM-A–/– mice.

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B cells and immunoglobulins in septic JAM-A–/– mice. (A–C) Percentage of...
(A–C) Percentage of B cells increased in both spleen (P = 0.002; n = 5 WT, n = 7 JAM-A–/–) and MLNs (P = 0.009; n = 10 WT, n = 10 JAM-A–/–) in KO mice but were similar in Peyer’s patches (P = 0.86; n = 12 WT, n = 12 JAM-A–/–). (D–G) Levels of serum IgA (P = 0.005; n = 12 WT, n = 12 JAM-A–/–) and IgG (P = 0.02; n = 11 WT, n = 9 JAM-A–/–) were both higher in septic JAM-A–/– mice, whereas IgM levels (P = 0.79; n = 10 WT, n = 11 JAM-A–/–) were similar and IgE levels (P = 0.006; n = 11 WT, n = 11 JAM-A–/–) were lower compared with WT mice. (H and I) Flow cytometry demonstrated increased frequency of IgA in intraepithelial lymphocytes (IELs) (representative flow plot; P = 0.04; n = 3 WT, n = 5 JAM-A–/–). (J) IgA levels also were increased in overall gut homogenate (P = 0.02; n = 7 WT, n = 10 JAM-A–/–). (K) Septic JAM-A–/– × RAG–/– mice had significantly improved survival compared with RAG–/– mice, although survival was similar between JAM-A–/– × RAG–/– mice and WT mice, despite the latter having worse survival than JAM-A–/– mice, as shown in Figure 2G (RAG–/–: P = 0.02, n = 22 WT, n = 19; JAM-A–/– × RAG–/–: n = 14 JAM-A–/– × RAG–/–). (A–G, I, and J) Data were subjected to a 1-tailed t testand Mann-Whitney U test depending on presence of Gaussian distribution. (K) Log-rank test was applied to the data. *P < 0.05, **P < 0.01.