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.

Klebsiella pneumoniae Outer Membrane Protein A Is Required to Prevent the Activation of Airway Epithelial Cells

“…Our findings further sustain the notion that airway epithelial cells orchestrate a defense response upon pathogen challenge by activating NF-B-and MAPK-dependent signaling pathways (56). In fact, activation of these pathways seems to be a central event of pathogen-exposed epithelial cells lining mucosal surfaces.…”

Nutritional modulation of the gut microbiota and immune system in preterm neonates susceptible to necrotizing enterocolitis

“…To date, there are 13 identified TLRs that recognize an assortment of PAMPs [i.e., lipopolysaccharide (TLR-4), peptidoglycan (TLR-2), flagellin (TLR-5) and bacterial DNA (TLR-9)]. All currently recognized TLRs are homologous with the IL-1 receptor, sharing an intracellular signaling domain, known as the Toll/IL-1R domain [131]. For example, the interaction of TLR-4 with lipolysaccharide leads to the activation of myeloid differentiation primary response protein 88-dependent signaling, resulting in the induction of pro-inflammatory genes such as TNF-α, IL-1β and IL-6 [132] (Fig.…”

“…Epithelial-bacterial interactions that may occur via TLRs are likely to play roles in the regulation of processes that regulate barrier integrity, such as epithelial migration, proliferation, and apoptosis. During states of stress, such as hypoxia, TLR signaling becomes exaggerated in response to ligands, thus favouring mucosal barrier disruption and adversely affecting mucosal repair while worsening mucosal injury [131]. In recent proteomics studies on preterm pig intestinal tissue, we showed that heat shock proteins (e.g., HSP60 and GRP78) were increased after just 8 h of formula feeding [79,136,137], suggesting that stress proteins released in response to formula feeding may initiate the inflammatory cascade through TLRs.…”

Chemokine response induced by Chlamydia trachomatis in prostate derived CD45+ and CD45− cells

“…Expression of different pattern recognition receptors (PRRs) at mucosal surfaces is central to innate immune defences (Hall et al 2002, Gribar et al 2008, Saenz et al 2008. Among these PRRs, toll-like receptors (TLRs) have been the most extensively studied (Akira & Takeda 2004, Delbridge & O'Riordan 2007.…”