Abstract
Tetraspanins are a family of proteins with four transmembrane domains that associate between themselves and cluster with other partner proteins, conforming a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs). These TEMs constitute macromolecular signaling platforms that regulate key processes in several cellular settings controlling signaling thresholds and avidity of receptors. In this study, we investigated the role of CD9, a tetraspanin that regulates major biological processes such as cell migration and immunological responses, in two mouse models of colitis that have been used to study the pathogenesis of inflammatory bowel disease (IBD). Previous in vitro studies revealed an important role in the interaction of leukocytes with inflamed endothelium, but in vivo evidence of the involvement of CD9 in inflammatory diseases is scarce. Here, we studied the role of CD9 in the pathogenesis of colitis in vivo. Colitis was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen that causes epithelial disruption and intestinal inflammation. CD9−/− mice showed less severe colitis than wild-type counterparts upon exposure to DSS (2% solution) and enhanced survival in response to a lethal DSS dose (4%). Decreased neutrophil and macrophage cell infiltration was observed in colonic tissue from CD9−/− animals, in accordance with their lower serum levels of TNF-α, IL-6, and other proinflammatory cytokines in the colon. The specific role of CD9 in IBD was further dissected by transfer of CD4+ CD45RBhi naive T cells into the Rag1−/− mouse colitis model. However, no significant differences were observed in these settings between both groups, ruling out a role for CD9 in IBD in the lymphoid compartment. Experiments with bone marrow chimeras revealed that CD9 in the non-hematopoietic compartment is involved in colon injury and limits the proliferation of epithelial cells. Our data indicate that CD9 in non-hematopoietic cells plays an important role in colitis by limiting epithelial cell proliferation. Future strategies to repress CD9 expression may be of therapeutic benefit in the treatment of IBD.
Highlights
Inflammatory bowel disease (IBD) defines a group of intestinal disorders, principally, ulcerative colitis (UC) and Crohn’s disease (CD)
CD9−/− Mice Are Protected against dextran sodium sulfate (DSS)-Induced Colonic Injury
CD9−/− animals lost less than 10% of their initial body weight, whereas WT counterparts lost around 20% (Figure 1A, top)
Summary
Inflammatory bowel disease (IBD) defines a group of intestinal disorders, principally, ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are characterized by chronic inflammation of the gastrointestinal tract interspersed with relapsing phases [1]. Role of Tetraspanin CD9 in Experimental Colitis studies in patients; these diseases remain incompletely understood. Identified genetic risk loci have revealed defects in IBD patients affecting genes crucial for intestinal homeostasis, including epithelial barrier function, restitution, and wounding [2]. Tetraspanins are proteins that span the cell membrane four times and play an important role in plasma membrane organization through the formation of tetraspanin-enriched microdomains, which enable them to associate with multiple proteins, including other tetraspanins [6]. We show that CD9 acts as a limiting factor for epithelial regeneration and colonic MH in dextran sodium sulfate (DSS)induced colitis
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