Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA.
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2018 Apr 25;19(5):1279. doi: 10.3390/ijms19051279.
Mast cells are key players in the development of inflammatory allergic reactions. Cross-linking of the high-affinity receptor for IgE (FcεRI) on mast cells leads to the generation and secretion of the sphingolipid mediator, sphingosine-1-phosphate (S1P) which is able, in turn, to transactivate its receptors on mast cells. Previous reports have identified the expression of two of the five receptors for S1P on mast cells, S1P₁ and S1P₂, with functions in FcεRI-mediated chemotaxis and degranulation, respectively. Here, we show that cultured mouse mast cells also express abundant message for S1P₄. Genetic deletion of did not affect the differentiation of bone marrow progenitors into mast cells or the proliferation of mast cells in culture. A comprehensive characterization of IgE-mediated responses in S1P₄-deficient bone marrow-derived and peritoneal mouse mast cells indicated that this receptor is dispensable for mast cell degranulation, cytokine/chemokine production and FcεRI-mediated chemotaxis in vitro. However, interleukin-33 (IL-33)-mediated enhancement of IgE-induced degranulation was reduced in S1P₄-deficient peritoneal mast cells, revealing a potential negative regulatory role for S1P₄ in an IL-33-rich environment. Surprisingly, genetic deletion of resulted in exacerbation of passive systemic anaphylaxis to IgE/anti-IgE in mice, a phenotype likely related to mast cell-extrinsic influences, such as the high circulating levels of IgE in these mice which increases FcεRI expression and consequently the extent of the response to FcεRI engagement. Thus, we provide evidence that S1P₄ modulates anaphylaxis in an unexpected manner that does not involve regulation of mast cell responsiveness to IgE stimulation.
肥大细胞是炎症性过敏反应发展的关键参与者。IgE 的高亲和力受体（FcεRI）交联导致鞘脂介质神经酰胺-1-磷酸（S1P）的产生和分泌，而 S1P 反过来又能够在肥大细胞上转激活其受体。先前的报告已经确定了肥大细胞上五个 S1P 受体中的两个，S1P1 和 S1P2 的表达，它们分别在 FcεRI 介导的趋化和脱颗粒中发挥作用。在这里，我们表明培养的小鼠肥大细胞也表达丰富的 S1P4 信使。缺失不会影响骨髓祖细胞分化为肥大细胞或培养中的肥大细胞增殖。对 IgE 介导的反应进行全面表征表明，该受体对于肥大细胞脱颗粒、细胞因子/趋化因子产生和 FcεRI 介导的趋化作用在体外是可有可无的。然而，在 S1P4 缺陷的腹腔肥大细胞中，白细胞介素-33（IL-33）介导的 IgE 诱导的脱颗粒增强作用降低，揭示了 S1P4 在富含 IL-33 的环境中可能具有负调节作用。令人惊讶的是，缺失导致对 IgE/抗 IgE 的被动全身性过敏反应在小鼠中加重，这种表型可能与肥大细胞外在影响有关，例如这些小鼠中循环 IgE 水平升高，增加了 FcεRI 的表达，从而增加了对 FcεRI 结合的反应程度。因此，我们提供的证据表明，S1P4 以一种出乎意料的方式调节过敏反应，而不涉及调节肥大细胞对 IgE 刺激的反应性。
