Datta, A; (2013) The role of thymic stromal lymphopoietin in pulmonary fibrosis. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Thymic stromal lymphopoietin (TSLP) is an IL-7 like cytokine that has recently emerged as being critical in promoting T-2 mediated inflammatory responses in atopic disease via its unique activation of dendritic cells (DCs). However, its role in idiopathic pulmonary fibrosis (IPF), a non-allergen driven disease characterised by excessive fibroblast activation and a pro-fibrotic T-2 immune phenotype, is unknown. TSLP has traditionally been regarded as an epithelial-derived cytokine targeting cells of a haematopoietic lineage. However, the present work identifies fibroblasts as a potentially important source and cellular target in IPF. Primary human lung fibroblasts (pHLFs) express and release TSLP in a JNK/c-Jun dependent manner following exposure to TNF-α, a master cytokine strongly implicated in the pathogenesis of lung fibrosis. Moreover, this thesis demonstrates for the first time that lung fibroblasts express a functional TSLP-TSLPR signalling axis; following exposure to TSLP, these cells release the pro-fibrotic chemokine, CCL2, in a STAT3-dependent manner, thereby promoting chemotaxis of human monocytes. The work presented here further identifies TSLP as a key mediator of local DC activation and the generation of a T-2 immune phenotype in the bleomycin model of lung injury and fibrosis. However, neutralisation of TSLP activity in vivo did not attenuate bleomycin-induced fibrosis, suggesting that despite its essential role in DC activation and T-2 polarisation, TSLP may not play a significant role in the subsequent development of fibrosis in this model. Taken together, these studies extend our current understanding of TSLP as a master regulator of T-2 immune responses beyond that of allergic inflammatory conditions. The human expression and functional studies performed during the course of this PhD do not rule out a potential pathogenic role for TSLP in IPF. Extended studies are warranted to explore these observations further.

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