NO LONGER AN INNOCENT BYSTANDER: EPITHELIAL TOLL-LIKE RECEPTOR SIGNALING IN THE DEVELOPMENT OF MUCOS
June 29th, 2008 | by admin |NO LONGER AN INNOCENT BYSTANDER: EPITHELIAL TOLL-LIKE RECEPTOR SIGNALING IN THE DEVELOPMENT OF MUCOSAL INFLAMMATION.
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 (TLR\’s) of the innate immune system, and that activation of TLR\’s 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 TLR\’s 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 TLR\’s 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.
Gribar SC, Richardson WM, Sodhi CP, Hackam DJ.
Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh and the University of Pittsburgh School of Medicine.