JAM-A regulates permeability and inflammation in the intestine in vivo

Abstract

Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A–deficient (JAM-A−/−) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A−/− mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A−/− mice. The in vivo observations were epithelial specific, because monolayers of JAM-A−/− epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A−/− mice and in JAM-A small interfering RNA–treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A−/− mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A−/− animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation.

Dietary riboflavin deficiency decreases immunity and antioxidant capacity, and changes tight junction proteins and related signaling molecules mRNA expression in the gills of young grass carp (Ctenopharyngodon idella)

“…acted as barrier-forming TJ proteins in fish [22,23,73], whereas Claudin-12 and Claudin-15 acted as pore-forming TJ proteins in mice [74]. Moreover, studies showed that decreased Claudin-b, -3, Occludin and ZO-1 mRNA levels in fish [23], and up-regulated Claudin-12 and Claudin-15 gene expression in mice [75,76] impaired TJ barrier function. Present study showed that compared with appropriate riboflavin supplementation, riboflavin deficiency up-regulated Claudin-12 and down-regulated Claudin-c, -3, Occludin and ZO-1 mRNA expression in the gills of young grass carp ( Fig.…”

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

“…JAM‐A regulates apical actomyosin contraction, and deficiencies lead to enhanced MLC2 phosphorylation 36. However, unlike in mice with JAM‐A deficiency 35, CerS2 null mice did not show increased epithelial proliferation and formation of large lymphoid aggregates. A possible explanation for this is that JAM‐A was only partially decreased in the colons of CerS2 null mice.…”

“…Mucin dysfunction 33, 34 and JAM‐A deficiency 35, 36 have been shown to cause increased intestinal permeability, especially under basal conditions, with an enhanced susceptibility to experimental colitis. Thus, we evaluated mucin production in CerS2 null mice.…”

“…The epithelial cells lining the gastrointestinal tract are connected via desmosomes and gap junctions, as well as tight and adherens junctions 37, 38, which comprise the apical junctional complex that is generally believed to play an essential role in maintaining the epithelial barrier 37. In apical junctional complexes in CerS2 null mice, the expression of JAM‐A, which has been implicated in the regulation of barrier function and leucocyte migration 35, was significantly reduced with and without DSS treatment compared to WT mice (Fig. 7A and B).…”

“…As with CerS2 null mice, mice deficient in JAM‐A exhibit increased basal intestinal permeability with normal epithelial architecture 35. JAM‐A regulates apical actomyosin contraction, and deficiencies lead to enhanced MLC2 phosphorylation 36.…”