Bin1: a new player in IBD barrier dysfunction.

The ability of the host to regulate permeability of the intestinal barrier is a critical determinant of host defense. Regulation of permeability occurs at the level of epithelial tight junctions (TJ). TJ are composed of transmembrane proteins, such as occludin, claudin, and JAM family proteins. Plaque proteins, such as zonula occludins (ZO), connect the TJ complex to F-actin and actomyosin rings regulating cytoskeletal reorganization (Fig. 1, reviewed in [1]). Several signaling pathways, such as myosin light chain kinase (MLCK), protein kinase C (PKC), mitogenactivated protein kinases (MAPK), and the Rho family of small GTPases, control the remodeling and maintenance of TJ. TJ not only regulate paracellular transport of nutrients and water, but they also provide a barrier against enteric microbes. Although the exact etiology is unknown, there is ample evidence that epithelial barrier function is compromised in inflammatory bowel disease (IBD) patients. Data from various studies using inert non-metabolized probes indicate that paracellular permeability is increased in Crohn’s Disease (CD) [2]. Furthermore, increased permeability may precede the onset of inflammation [3]. Researchers also found that enteric permeability is increased in 10–54 % of healthy, first-degree relatives of IBD patients [4, 5]. To date, several studies have associated IBD with mutations in the NOD2 gene [6, 7]. However, NOD2 penetrance of the most at-risk genotypes is low [8], and it is likely that cooperation with other genetic factors, such as TJ defects, is required for disease development. Interestingly, Buhner et al. detected increased permeability in IBD patients and family members with NOD2 mutations [9]. Altogether, these findings support the speculation that altered permeability constitutes one of several genetically determined variables that enhances the risk for developing IBD. The notion that altered epithelial permeability predisposes patients to IBD is supported by data from several animal models with transmucosal barrier defects. Using transgenic mice that express constitutively active MLCK, Su et al. demonstrated that, while insufficient to fully induce experimental colitis alone, TJ defects exacerbated disease in the adoptive transfer colitis model [10]. Other models of barrier disruption, such as dominant negative N-cadherin expression, resulted in spontaneous inflammation [11], further enforcing the link between barrier dysfunction and immune homeostasis. Altered permeability may also occur due to effects of local cytokines. Tumor necrosis factor, a cytokine critical for the pathogenesis of IBD, activates MLCK, resulting in TJ disruption via internalization of occludin from the cell membrane [12]. Also, interleukin-13, a cytokine upregulated in ulcerative colitis, induces expression of the pore-forming TJ protein claudin-2, leading to barrier dysfunction [13]. Altogether, these data represent the dynamic relationship between inflammation and permeability and how their imbalance may result in the development of IBD. In this issue of Digestive Diseases and Sciences, Chang et al. present data that further support the tie between TJ permeability and IBD pathogenesis via the protein Bridging integrator 1 (Bin1) [14]. Bin1 is a member of the Bin amphiphysin rys (BAR) adaptor family with myriad H. Ryu D. Posca T. Barrett (&) Department of Internal Medicine, Division of Gastroenterology, Northwestern University Feinberg School of Medicine, 300 E. Chicago Ave., Tarry 4-725, Chicago, IL 60611, USA e-mail: tabarrett@northwestern.edu