Evidence for a Functional Thymic Stromal Lymphopoietin Signaling Axis in Fibrotic Lung Disease

Abstract

Thymic stromal lymphopoietin (TSLP) recently has emerged as a key cytokine in the development of type 2 immune responses. Although traditionally associated with allergic inflammation, type 2 responses are also recognized to contribute to the pathogenesis of tissue fibrosis. However, the role of TSLP in the development of non-allergen-driven diseases, characterized by profibrotic type 2 immune phenotypes and excessive fibroblast activation, remains underexplored. Fibroblasts represent the key effector cells responsible for extracellular matrix production but additionally play important immunoregulatory roles, including choreographing immune cell recruitment through chemokine regulation. The aim of this study was to examine whether TSLP may be involved in the pathogenesis of a proto-typical fibrotic disease, idiopathic pulmonary fibrosis (IPF). We combined the immunohistochemical analysis of human IPF biopsy material with signaling studies by using cultured primary human lung fibroblasts and report for the first time, to our knowledge, that TSLP and its receptor (TSLPR) are highly upregulated in IPF. We further show that lung fibroblasts represent both a novel cellular source and target of TSLP and that TSLP induces fibroblast CCL2 release (via STAT3) and subsequent monocyte chemotaxis. These studies extend our understanding of TSLP as a master regulator of type 2 immune responses beyond that of allergic inflammatory conditions and suggest a novel role for TSLP in the context of chronic fibrotic lung disease.