Abstract
Thymic stromal lymphopoietin (TSLP) is released by epithelial cells following disturbed homeostasis to act as “alarmin” and driver of Th2-immunity. Aberrant TSLP expression is a hallmark of atopic diseases, including atopic dermatitis (AD). Mast cells (MCs) are overabundant in AD lesions and show signs of degranulation, but it remains unknown whether TSLP contributes to granule discharge. Degranulation of skin MCs proceeds via two major routes, i.e., FcεRI-dependent (allergic) and MRGPRX2-mediated (pseudo-allergic/neurogenic). Evidence is accumulating that MRGPRX2 may be crucial in the context of skin diseases, including eczema. The current study reveals TSLP as a novel priming factor of human skin MCs. Interestingly, TSLP selectively cooperates with MRGPRX2 to support granule discharge, while it does not impact spontaneous or FcεRI-driven exocytosis. TSLP-assisted histamine liberation triggered by compound 48/80 or Substance P, two canonical MRGPRX2 agonists, was accompanied by an increase in CD107a+ cells (a MC activation marker). The latter process was less potent, however, and detectable only at the later of two time points, suggesting TSLP may prolong opening of the granules. Mechanistically, TSLP elicited phosphorylation of STAT5 and JNK in skin MCs and the reinforced degranulation critically depended on STAT5 activity, while JNK had a contributory role. Results from pharmacological inhibition were confirmed by RNA-interference, whereby silencing of STAT5 completely abolished the priming effect of TSLP on MRGPRX2-mediated degranulation. Collectively, TSLP is the first factor to favor MRGPRX2- over FcεRI-triggered MC activation. The relevance of TSLP, MCs and MRGPRX2 to pruritis and atopic skin pathology indicates broad repercussions of the identified connection.
Highlights
Acute mast cell (MC) activation leads to hypersensitivity reactions and is the root of disorders like rhinoconjunctivitis, asthma, urticaria, angioedema, food allergy, and anaphylaxis [1,2]
MCs were the most efficient producers of the TSLPR transcript in the FANTOM5 (Functional annotation of the mammalian genome 5) atlas, a transcriptome collection of roughly 1800 cell and tissue samples from all across the body, pointing towards MCs as meaningful target cells [17,42,43]. Following up on this finding, we recently reported that Thymic stromal lymphopoietin (TSLP) efficiently maintains survival of skin MCs by acting through a complex mechanism composed of two parallel axes, i.e., STAT5/Mcl-1 and JNK/Bcl-xl [44]
MCs adjust their responsiveness to secretory stimuli in dependence of the tissue microenvironment, whereby modulating factors like cytokines can critically influence their secretory competence without acting as secretagogues on their own
Summary
Acute mast cell (MC) activation leads to hypersensitivity reactions and is the root of disorders like rhinoconjunctivitis, asthma, urticaria, angioedema, food allergy, and anaphylaxis [1,2]. Relevant MC activation can be evoked by the allergic route involving FcεRI, IgE, and allergen, or by the more recently discovered MAS-related G protein coupled receptorX2 (MRGPRX2)-dependent pathway The latter receptor can be activated by a wide range of agonists, including neuropeptides (e.g., Substance P) and exogenous substances (like compound 48/80, antibiotics, opiates) [3,4,5,6,7,8]. MCs were the most efficient producers of the TSLPR transcript (gene: CRLF2) in the FANTOM5 (Functional annotation of the mammalian genome 5) atlas, a transcriptome collection of roughly 1800 cell and tissue samples from all across the body, pointing towards MCs as meaningful target cells [17,42,43] Following up on this finding, we recently reported that TSLP efficiently maintains survival of skin MCs by acting through a complex mechanism composed of two parallel axes, i.e., STAT5/Mcl-1 and JNK/Bcl-xl [44]. TSLP support was orchestrated by the dominant action of STAT5 with further support from JNK, the two cascades most prominently activated by TSLP in skin MCs [44]
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