Barrier-protective function of intestinal epithelial Toll-like receptor 2

Abstract

The intestinal epithelial cell (IEC) barrier plays an important role in maintaining mucosal immune homeostasis. Dysregulated IEC barrier function appears to trigger and perpetuate inflammation in inflammatory bowel diseases (IBD). Novel risk variants in the Toll-like receptor 2 (TLR2) gene have previously been associated with a more severe disease phenotype in a subgroup of IBD patients. Recent studies have provided important insights of the commensal and host defense mechanisms to maintain functional barrier integrity of the intestinal epithelium through TLR2. Deficient TLR2 signaling may imbalance commensal-dependent intestinal epithelial barrier defense, facilitating mucosal injury and leading to increased susceptibility of colitis. Treatment with a synthetic TLR2 ligand significantly suppresses mucosal inflammation by efficiently protecting tight junction-associated integrity of the intestinal epithelium in vivo. These beneficial effects may be supplemented by TLR2-induced anti-inflammatory immune responses (such as interleukin-10 production) in lamina propria mononuclear cells. Thus, cell-specific TLR2 targeting may offer a novel therapeutic approach to human IBD therapy by protecting IEC barrier function.

Does TLR2 regulate intestinal inflammation?

“…Colitis initiated by DSS, ischaemia or by toxic disruption of tight junctions is exacerbated in mice lacking TLR2 and administration of TLR2 ligands can ameliorate DSS colitis. These TLR2-dependent properties appear to be due to cytoprotective effects on epithelial cells, including stimulation of stem cell growth, ZO-1-mediated tight junction formation, NF-kB-mediated prevention of apoptosis and gap junction stabilisation [12]. Although these findings are clearly at odds with those of Boulard et al [10], tellingly the earlier results came from models of colitis that are extremely acute in nature and in which the primary event is damage to the epithelium.…”

“…In particular, the findings challenge previous suggestions that TLR2 ligation plays a critical role in protective and pathogenic processes in intestinal inflammation [12]. TLR2 expression is upregulated in human IBD [13] and TLR2 has been reported to mediate activation of host cells by various Helicobacter spp.…”

Identification of TLR10 as a Key Mediator of the Inflammatory Response to Listeria monocytogenes in Intestinal Epithelial Cells and Macrophages

“…Whereas the primary role of TLRs in the intestine is the same as in other tissues (i.e., defense against infection), other homeostatic functions have been described. TLR2, for example, is found to be expressed on both apical and basolateral surfaces of intestinal epithelial cells, and activation of TLR2 from the apical surface has been reported to result in cell homeostasis, not inflammation (32). Similarly, MyD88 has been shown to have a homeostatic role in the epithelium, as mice lacking MyD88 are hyperresponsive to dextran sulfate sodium-induced colitis (33).…”

Tumor Necrosis Factor Alpha and Inflammation Disrupt the Polarity Complex in Intestinal Epithelial Cells by a Posttranslational Mechanism

“…Increased TJ permeability facilitates the diffusion of small antigens and bacterial toxins, which in turn can exacerbate or perpetuate the inflammatory process (8,29). Cytokines initiate proinflammatory signaling on intestinal epithelial cells in IBD, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and several interleukins (1,28,29).…”