JAM-A regulates permeability and inflammation in the intestine in vivo.
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.
Laukoetter
Mike G
MG
Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA 30322, USA.
Nava
Porfirio
P
Lee
Winston Y
WY
Severson
Eric A
EA
Capaldo
Christopher T
CT
Babbin
Brian A
BA
Williams
Ifor R
IR
Koval
Michael
M
Peatman
Eric
E
Campbell
Jacquelyn A
JA
Dermody
Terence S
TS
Nusrat
Asma
A
Parkos
Charles A
CA
D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology*; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism*; D004848:Epithelium / Q000196:embryology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D010539:Permeability; D011956:Receptors, Cell Surface / Q000502:physiology*
D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface