Co-operative regulation of epithelial homeostasis and immunity

Epithelium of barrier organs plays a primary host defense function. In the lung, airway epithelium protects from respiratory pathogens routinely present in the air without development of excessive inflammation or tissue injury. We hypothesized that such a barrier function might be achieved due to a...

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Bibliographische Detailangaben
1. Verfasser: Shaykhiev, Renat
Beteiligte: Bals, Robert (Dr. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2007
Innere Medizin
Schlagworte:
TLR
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Zusammenfassung:Epithelium of barrier organs plays a primary host defense function. In the lung, airway epithelium protects from respiratory pathogens routinely present in the air without development of excessive inflammation or tissue injury. We hypothesized that such a barrier function might be achieved due to a co-operation of immunoregulatory and tissue repair mechanisms. Consistent with such a concept, in the present study we identified multiple links between innate immunity and epithelial homeostasis using airway epithelium as a model. First, we found that, at physiologically relevant concentrations, the endogenous antimicrobial peptide LL-37 exerts protective effects on airway mucosal cells by inducing epithelial cell (EC) migration, proliferation, wound closure, and by regulation of inflammatory responses of ECs and dendritic cells (DCs) induced by microbial signals. High concentrations of LL-37 (> 20 μg/ml) were toxic for airway ECs. Second, innate immune recognition of microbial patterns by airway ECs initiated repair (cell migration, wound closure) and growth (cell proliferation, survival) events in epithelium independently on cells of myeloid origin. Microbial patterns signaling via toll-like receptor (TLR) – MyD88 – NF-kappa B pathway showed the most prominent effect on epithelial homeostasis. Epidermal growth factor receptor (EGFR) is involved in epithelial repair responses induced by LL-37 or epithelial TLR signals. Particular sensitivity of epithelial cancer cells to growth-promoting effects of TLR agonists suggests that epithelial TLRs might be involved in autonomous cancer cell growth. Finally, in an in vitro model of interaction of DCs with differentiated airway epithelium, ECs were able to control DC activation by prevention of a direct contact with bacteria and / or due to the regulatory properties of soluble factors which are released by ECs. DCs “educated” within airway epithelial microenvironment were substantially less sensitive to stimulation with microbial factors. Prolonged presence of monocyte-derived DCs beneath airway epithelium significantly increased epithelial permeability, suggesting that bidirectional interactions between ECs and DCs exist and may potentially modulate epithelial barrier function and mucosal tissue homeostasis. Taken together, epithelial homeostasis and innate immunity are closely connected, and their co-operative regulation is involved in the maintenance of tissue integrity and immune balance. Understanding of such a mechanism might be important for further progress in the development of novel therapeutic approaches to chronic diseases (asthma, interstitial lung diseases, inflammatory bowel disease, cancer and others), which are associated with concomitant immune dysregulation and epithelial tissue injury.