Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Cell Degranulation*; Cytokines/*metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mast Cells/*physiology ; Nerve Tissue Proteins/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Receptors, Neuropeptide/*metabolism ; STAT5 Transcription Factor/*metabolism ; Skin/*pathology; Histamine Release ; Humans ; Lysosomal-Associated Membrane Protein 1/metabolism ; Male ; RNA Interference ; Reproducibility of Results ; Thymic Stromal Lymphopoietin

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.

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Keywords: MRGPRX2; Substance P; TSLP; mast cell; pseudo-allergy; skin

0 (Cytokines)
0 (Lysosomal-Associated Membrane Protein 1)
0 (MRGPRX2 protein, human)
0 (Nerve Tissue Proteins)
0 (Receptors, G-Protein-Coupled)
0 (Receptors, Neuropeptide)
0 (STAT5 Transcription Factor)
EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
GT0IL38SP4 (Thymic Stromal Lymphopoietin)

Date Created: 20210112 Date Completed: 20210826 Latest Revision: 20221207

20231215

PMC7826995

10.3390/cells10010102

33429916