Palestra, Francesco (2025) THYMIC STROMAL LYMPHOPOIETIN (TSLP) IN HUMAN LUNG MACROPHAGES: EXPRESSION, SECRETION, AND REGULATION BY MAST CELL PROTEASES. [Tesi di dottorato]

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Abstract

Thymic stromal lymphopoietin (TSLP) is a cytokine secreted from epithelial cells and plays a role in central airway inflammation and remodeling. Although the airway epithelium has been classically considered to be its main source, recent evidence points to the possibility that other cell types may also be capable of secreting TSLP in a situation of inflammation. In the current research, we investigated the expression, secretion, and regulation of TSLP in human lung macrophages (HLMs) and tested if mast cell–derived proteases play a role in modulating its biological effect. Subcellular fractionation and confocal microscopy of HLMs established that TSLP is predominantly cytoplasmic, with no subcellular fractionation to the nucleus. Type-2 cytokines (IL-4 and IL-13) and bacterial lipopolysaccharide (LPS) stimulated de novo production and secretion of TSLP, with minimal induction by IL-13 alone. These findings establish that macrophages react to both T2-high and T2-low stimuli and play an active role in airway inflammation. Functional assays showed that the long TSLP isoform (lfTSLP) by itself elicited the release of vascular endothelial growth factor-A (VEGF-A) from HLMs while the short form (sfTSLP) was inactive and non antagonistic. We further found that mast cell proteases tryptase and chymase efficiently cleaved TSLP, generating fragments that are not biologically active on macrophages. Such proteolytic regulation will predominantly function as a feedback mechanism to limit the availability of localized cytokines. In combination, our data identify human lung macrophages as a novel source and target of TSLP and unveil an epithelial cell/macrophage/mast cell-dependent regulatory loop. The tri-cellular loop may play a role in the maintenance of chronic low-grade airway inflammation and provides novel opportunities for therapeutic targeting of TSLP in asthma and COPD.

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