The “polarizing–tolerizing” mechanism of intestinal epithelium: its relevance to colonic homeostasis

Recent data indicate that stimulation of Toll-like receptors (TLRs) by intestinal microbiota supports colonic homeostasis. Intestinal epithelial cells (IECs) express several TLRs. It has been demonstrated that repeated exposure to TLR ligands causes IECs to become hypo-responsive. Inhibition of TLR cell surface expression and the induction of inhibitory intracellular signaling molecules have been proposed to mediate this state of tolerance to luminal commensals and/or their TLR ligands. In this review, we summarize our recent observations that uncover the essential role of IEC polarization in the homeostatic response of IECs to TLR ligands. In particular, apical TLR9 stimulation delivers negative signals that curtail inflammatory responses induced by basolateral stimulation by other TLRs. This “polarizing–tolerizing” ability of IECs represents a unique mechanism that restrains inflammatory responses in a bacteria-rich environment. Thus, interventions that enhance IEC polarization could prevent or inhibit human inflammatory bowel diseases and other types of intestinal inflammation.