The Regulation and Function of Thymic Stromal Lymphopoietin Receptor (TSLPR) in the Airway Epithelium

Abstract

The epithelially-derived cytokine thymic stromal lymphopoietin (TSLP) plays a key role in the development and progression of allergic disease and has notably been shown to directly promote the inflammatory responses that characterize asthma. Current models suggest that TSLP is produced by epithelial cells in response to inflammatory stimuli and acts upon hematopoietic cells to effect a T_H2-type inflammatory response. Recent reports, however, have shown that epithelial cells themselves are capable of expressing the TSLP receptor (TSLPR), and may thus directly contribute to a TSLP-dependent response. In this thesis, we review what is known about both the immunological and epithelial responses that contribute to the pathogenesis of asthma, and further present novel data indicating a role for epithelially expressed TSLPR to play in those responses. We present data that epithelial cells indeed express a glycosylated form of the TSLP receptor. Furthermore, we find that beyond simply expressing TSLPR, epithelial cells are capable of dynamically regulating TSLPR in response to the same inflammatory cues that drive the production of TSLP. This induced receptor is functional, as epithelial cells produce CCL17, a T_H2-associated chemokine, in response to stimulation with TSLP. These data suggest that a direct autocrine or paracrine response to TSLP by epithelial cells may initiate the first rounds of chemotaxis during an allergic inflammatory response. Intriguingly, we find that the regulation of TSLPR, unlike TSLP, is NF-κB independent, suggesting that the cell may be able to independently regulate TSLP and TSLPR levels in order to properly modulate its response to TSLP. Finally, we show evidence for this dynamic regulation occurring following the viral infection of primary epithelial cells from asthmatic patients. Taken together, the data suggest that induction of TSLPR and a direct response to TSLP by epithelial cells may play a novel role in the development of allergic inflammation.