CREB Is Critically Implicated in Skin Mast Cell Degranulation Elicited via FcεRI and MRGPRX2.

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

Mast Cells*/metabolism ; Mast Cells*/immunology ; Cell Degranulation* ; Cyclic AMP Response Element-Binding Protein*/metabolism ; Receptors, Neuropeptide*/metabolism ; Receptors, Neuropeptide*/genetics ; Nerve Tissue Proteins*/metabolism ; Nerve Tissue Proteins*/genetics ; Receptors, G-Protein-Coupled*/metabolism ; Receptors, G-Protein-Coupled*/genetics ; Receptors, IgE*/metabolism ; Skin*/metabolism; Humans ; Animals ; Mice

Skin mast cells (MCs) mediate acute allergic reactions in the cutaneous environment and contribute to chronic dermatoses, including urticaria, and atopic or contact dermatitis. The cAMP response element binding protein (CREB), an evolutionarily well conserved transcription factor (TF) with over 4,000 binding sites in the genome, was recently found to form a feedforward loop with KIT, maintaining MC survival. The most selective MC function is degranulation with its acute release of prestored mediators. Herein, we asked whether CREB contributes to the expression and function of the degranulation-competent receptors FcεRI and MRGPRX2. Interference with CREB by pharmacological inhibition (CREBi, 666-15) or RNA interference only slightly affected the expression of these receptors, while KIT was strongly attenuated. Interestingly, MRGPRX2 surface expression moderately increased following CREB-knockdown, whereas MRGPRX2-dependent exocytosis simultaneously decreased. FcεRI expression and function were regulated consistently, although the effect was stronger at the functional level. Preformed MC mediators (tryptase, histamine, β -hexosaminidase) remained comparable following CREB attenuation, suggesting that granule synthesis did not rely on CREB function. Collectively, in contrast to KIT, FcεRI and MRGPRX2 moderately depend on unperturbed CREB function. Nevertheless, CREB is required to maintain MC releasability irrespective of stimulus, insinuating that CREB may operate by safeguarding the degranulation machinery. To our knowledge, CREB is the first factor identified to regulate MRGPRX2 expression and function in opposite direction. Overall, the ancient TF is an indispensable component of skin MCs, orchestrating not only survival and proliferation but also their secretory competence.

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BA-3769/3 and BA-3769/4 Deutsche Forschungsgemeinschaft; no grant number Charité - Universitätsmedizin Berlin; no grant number European Center for Allergy Research Foundation; no grant number China Scholarship Council

Keywords: CREB; FcεRI; MRGPRX2; RNA interference; RTqPCR; degranulation; flow cytometry; mast cell; skin

0 (Cyclic AMP Response Element-Binding Protein)
0 (Receptors, Neuropeptide)
0 (Nerve Tissue Proteins)
0 (Receptors, G-Protein-Coupled)
0 (Receptors, IgE)
0 (MRGPRX2 protein, human)

Date Created: 20241025 Date Completed: 20241025 Latest Revision: 20241027

20241027

PMC11506305

10.3390/cells13201681

39451199