Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany.
Institute of Allergology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
Cells. 2024 Oct 11;13(20):1681. doi: 10.3390/cells13201681.
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, -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.
皮肤肥大细胞 (MCs) 在皮肤环境中介导急性过敏反应，并导致慢性皮肤病，包括荨麻疹以及特应性皮炎或接触性皮炎。cAMP 反应元件结合蛋白 (CREB) 是一种进化上高度保守的转录因子 (TF)，其基因组中具有超过 4000 个结合位点，最近发现它与 KIT 形成正反馈环，维持 MC 的存活。MC 最具选择性的功能是脱颗粒，伴随着其预先储存的介质的急性释放。在此，我们询问 CREB 是否有助于脱颗粒功能相关受体 FcεRI 和 MRGPRX2 的表达和功能。通过药理学抑制 (CREBi, 666-15) 或 RNA 干扰干扰 CREB 仅轻微影响这些受体的表达，而 KIT 则被强烈削弱。有趣的是，MRGPRX2 表面表达在 CREB 敲低后适度增加，而 MRGPRX2 依赖性胞吐作用同时减少。FcεRI 的表达和功能受到一致调节，尽管在功能水平上的影响更强。在 CREB 衰减后，预先形成的 MC 介质（类胰蛋白酶、组胺、β-己糖胺酶）保持相当，表明颗粒合成不依赖于 CREB 功能。总的来说，与 KIT 相比，FcεRI 和 MRGPRX2 适度依赖于未受干扰的 CREB 功能。然而，无论刺激如何，CREB 都需要维持 MC 的释放能力，这暗示 CREB 可能通过保护脱颗粒机制来发挥作用。据我们所知，CREB 是第一个被确定为调节 MRGPRX2 表达和功能的因子，其方向相反。总的来说，古老的 TF 是皮肤 MCs 不可或缺的组成部分，不仅协调生存和增殖，还协调它们的分泌能力。
