No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation

Abstract

Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

Figure 1

Mechanisms by which TLR signaling leads to mucosal inflammation. As stated in the text, there are two potential mechanisms by which TLR signaling can lead to the development of mucosal inflammation. (A) TLR activation in response to DAMPs (damage associated molecular patterns) and PAMPs (pathogen associated molecular patterns) on leukocytes leads to the release of pro-inflammatory cytokines, resulting in epithelial destruction. (B) TLR activation by DAMPs and PAMPs on the epithelium itself directly impairs epithelial function and initiates the release of cytokines, leading to the development of mucosal inflammation. The development of mucosal inflammation likely arises from a combination of these mechanisms.

Figure 2

TLR4 signaling pathways. LPS binding to TLR4 requires binding protein (LBP), MD-2, and the co-receptor CD-14 which initiates MyD88-dependent (blue) and MyD88-independent (yellow) signaling pathways. See text for details.

Figure 3

A model of TLR-mediated inflammation in the mucosa. (A) During basal conditions, TLR signaling is required for mucosal homeostasis. (B) Under conditions of physiological stress, TLR signaling in epithelial cells becomes exaggerated in part through increased TLR expression. This leads to an impairment in epithelial function, increased injury, and decreased repair, resulting in mucosal inflammation.