Department of Physiology, Michigan State University, East Lansing, MI 48824.
Department of Physiology, Michigan State University, East Lansing, MI 48824
J Immunol. 2021 Feb 1;206(3):471-480. doi: 10.4049/jimmunol.2000671. Epub 2020 Dec 23.
Mast cells are tissue-resident immune cells that play pivotal roles in initiating and amplifying allergic/anaphylactic reactions in humans. Their activation occurs via multiple mechanisms, which include cross-linking of the IgE-bound, high-affinity IgE receptors (FcεRI) by allergens or Ags and the binding of anaphylatoxins such as C3a to its receptor, C3aR. We have previously demonstrated that the Na/H exchanger regulatory factor 1 (NHERF1) promotes C3aR functions in human mast cells. In the current study, we show that NHERF1 regulates mast cell response following FcεRI stimulation. Specifically, intracellular Ca mobilization, activation of the MAPKs (ERK1/2 and P38), and production of cytokines (IL-13 and IL-6) following exposure to IgE/Ag were significantly reduced in mast cells from NHERF1 mice. In agreement with our in vitro data, mast cell-mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis were reduced in NHERF1 mice and mast cell-deficient mice engrafted with NHERF1 mast cells. Mechanistically, the levels of microRNAs (miRNAs) that regulate mast cell responses, miRNA 155-3p and miRNA 155-5p, were altered in mast cells from NHERF1 mice. Moreover, NHERF1 rapidly localized to the nucleus of mast cells following FcεRI stimulation. In summary, our results suggest that the NHERF1 acts as an adapter molecule and promotes IgE/Ag-induced mast cell activation. Further elucidating the mechanisms through which NHERF1 modulates mast cell responses will lend insights into the development of new therapeutic strategies to target mast cells during anaphylaxis or other allergic diseases.
肥大细胞是组织驻留免疫细胞，在人类中发挥着启动和放大过敏/过敏反应的关键作用。它们的激活通过多种机制发生，包括过敏原或抗原交联 IgE 结合的高亲和力 IgE 受体 (FcεRI)，以及过敏毒素如 C3a 与其受体 C3aR 的结合。我们之前已经证明，Na/H 交换调节剂因子 1 (NHERF1) 促进了人类肥大细胞中的 C3aR 功能。在当前的研究中，我们表明 NHERF1 调节肥大细胞在 FcεRI 刺激后的反应。具体而言，在 NHERF1 小鼠的肥大细胞中，细胞内 Ca 动员、MAPKs（ERK1/2 和 P38）的激活以及细胞因子（IL-13 和 IL-6）的产生在暴露于 IgE/Ag 后显著降低。与我们的体外数据一致，NHERF1 小鼠和移植了 NHERF1 肥大细胞的肥大细胞缺陷小鼠中的肥大细胞介导的被动皮肤过敏反应和被动全身性过敏反应减少。从机制上讲，调节肥大细胞反应的 microRNAs (miRNAs) 的水平，miRNA 155-3p 和 miRNA 155-5p，在 NHERF1 小鼠的肥大细胞中发生改变。此外，NHERF1 在 FcεRI 刺激后迅速定位于肥大细胞的核内。总之，我们的结果表明 NHERF1 作为衔接分子，促进 IgE/Ag 诱导的肥大细胞激活。进一步阐明 NHERF1 调节肥大细胞反应的机制将深入了解在过敏或其他过敏疾病期间靶向肥大细胞的新治疗策略的发展。
