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Increased Intestinal Permeability Secondary To Junctional Adhesion Molecule‐A Deficiency Results In Impaired Macrophage‐Dependent Neutrophil Recruitment In A Zymosan Peritonitis Model
Author(s) -
Luissint Anny Claude,
Williams Holly C,
Kim Wooki,
Hilgarth Roland S,
O'Leary Monique,
Flemming Sven,
Reed Michelle,
Denning Timothy L,
Nusrat Asma,
Parkos Charles A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.469.8
Subject(s) - zymosan , cxcl1 , chemokine , conditional gene knockout , peritoneum , immune system , immunology , knockout mouse , ccr2 , chemistry , chemotaxis , microbiology and biotechnology , in vivo , peritonitis , innate immune system , biology , medicine , in vitro , anatomy , biochemistry , receptor , phenotype , chemokine receptor , gene
JAM‐A is a transmembrane protein expressed on endothelial and epithelial cells as well as on the surface of leukocytes. Studies with JAM‐A knockout mice (JAM‐A −/− ), have provided evidence that JAM‐A may facilitate tissue recruitment of neutrophils (PMN); however mechanisms regulating JAM‐A‐dependent migration of PMN in‐vivo is not well understood. Here, we used a zymosan‐induced peritonitis model to study the recruitment of PMN in total knockout mice (JAM‐A −/− ) and compared results to those obtained in mice with tissue selective deletion of JAM‐A in myelomonocytic cells (LysMcre; JAM‐A fl/fl ) and the intestinal epithelium (Villin‐Cre; JAM‐A fl/fl ). Consistent with a previous report, infiltration of PMN in the peritoneum in response to zymosan was decreased in JAM‐A −/− versus JAM +/+ mice. Surprisingly, in LysMcre; JAM‐A fl/fl mice, the number of PMN recruited into the peritoneum was not significantly affected by the specific loss of JAM‐A in myeloid cells compared to control littermates. Given that zymosan is a potent stimulus for peritoneal macrophages, we investigated the effect of the loss of JAM‐A on macrophage immune responses. While peritoneal macrophages from JAM‐A +/+ and JAM‐A −/− mice were similarly capable of phagocytizing zymosan, JAM‐A −/− macrophages showed significantly decreased production of the PMN chemokine CXCL1/KC that was dependent on the transcription factor NFkB. Interestingly, zymosan‐stimulated production of immune mediators from macrophages was not significantly affected by the specific loss of JAM‐A in myelomonocytic cells. These findings suggested that extrinsic factors contribute to the defective PMN migration observed in zymosan exposed JAM‐A −/− mice. We thus hypothesized that blunted peritoneal macrophage responses in JAM‐A −/− mice may be secondary to the known increase in intestinal permeability and bacterial translocation in these mice. Comparison of peritoneal macrophage subsets in total knockout and tissue selective JAM‐A deficient mice (Villin‐Cre; JAM‐A fl/fl ) revealed increased numbers of poor CXCL1 producing macrophages (F4/80 low ) compared to high producers (F4/80 high ). Our results suggest that a leaky intestinal barrier and enhanced microbial translocation as observed in JAM‐A deficiency indirectly blunts neutrophil recruitment through effects on macrophage release of inflammatory mediators. Such observations highlight an important functional link between the intestinal barrier and regulation of innate immune responses. Support or Funding Information RO1 DK072564‐21