Increased circulating levels of neurotrophins and elevated expression of their high-affinity receptors on skin and gut mast cells in mastocytosis.

摘要

Mastocytosis is a rare heterogeneous disease characterized by increase of mast cells (MCs) in different organs. Neurotrophins (NTs) have been shown to promote differentiation and survival of MCs, which in turn represent a major source of NTs. Thus, a contribution of NTs to mastocytosis seems highly conceivable but has not yet been investigated. We could demonstrate expression of high-affinity NT receptors tropomyosin-related kinase A (TrkA) for nerve growth factor (NGF)-β, TrkB for brain-derived neurotrophic factor, and NT-4 and TrkC for NT-3 on skin MCs; and of TrkA and TrkC on intestinal MCs of patients with mastocytosis. Moreover, increased expression of NGF-β; NT-3; TrkA, TrkB, and TrkC; and isoforms truncated TrkB-T1 and truncated TrkC were observed on skin MCs. Patients with mastocytosis featured elevated serum levels of NGF, NT-3, and NT-4. Levels of NGF-β and NT-4 correlated with tryptase levels, suggesting a link between MC load and blood levels of NGF and NT-4. Migration of CD117+ progenitor cells from the blood was enhanced toward NGF-β gradient in both mastocytosis and controls. Together with enhanced NT levels, the elevated expression of modified Trk receptors on skin and gut MCs might contribute to the pathophysiology of mastocytosis in autocrine and paracrine loops.