Thymic stromal lymphopoietin (TSLP) is a substrate for tryptase in patients with mastocytosis

Abstract

Mastocytosis is a heterogeneous disease associated to uncontrolled proliferation and increased density of mast cells in different organs. This clonal disorder is related to gain-of-function pathogenic variants of the c-kit gene that encodes for KIT (CD117) expressed on mast cell membrane. Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, which plays a key role in allergic disorders and several cancers. TSLP is a survival and activating factor for human mast cells through the engagement of the TSLP receptor. Activated human mast cells release several preformed mediators, including tryptase. Increased mast cell-derived tryptase is a diagnostic biomarker of mastocytosis. In this study, we found that in these patients serum concentrations of TSLP were lower than healthy donors. There was an inverse correlation between TSLP and tryptase concentrations in mastocytosis. Incubation of human recombinant TSLP with sera from patients with mastocytosis, containing increasing concentrations of tryptase, concentration-dependently decreased TSLP immunoreactivity. Similarly, recombinant β-tryptase reduced the immunoreactivity of recombinant TSLP, inducing the formation of a cleavage product of approximately 10 kDa. Collectively, these results indicate that TSLP is a substrate for human mast cell tryptase and highlight a novel loop involving these mediators in mastocytosis.