PGD2/CRTH2 signaling promotes acquired immunity against bee venom by enhancing IgE production

IgE-dependent/independent activation of mast cell (MC) has been assumed to play a host defensive role against venom injection in skin. However, its detailed mechanisms remain unknown. We aimed to investigate the contribution of MC-derived prostaglandin D-2 (PGD(2))-mediated signaling in host defense against bee venom (BV). To achieve this, we utilized gene-deficient mice of a PGD(2) receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). We first confirmed that subcutaneous injection of BV produced PGD(2) equally in wild-type (WT) and CRTH2-deficient (Crth2(-/-)) mice skins. The BV injection dropped body temperature and impaired kidney equally in both lines of mice. In WT mice, pre-injection of BV (3 weeks) significantly inhibited the hypothermia and kidney impairment caused by second BV injection. In contrast, this pre-injection was not effective for the second BV injection in Crth2(-/-) mice. We also found that BV injections increased serum BV-specific IgE levels in WT mice, and its serum transfused mice improved the BV-induced hypothermia in naive WT mice. In contrast, serum BV-specific IgE level was significantly lower in Crth2(-/-) mice. FACS analysis showed the BV injection stimulate migration of dendritic cells (DCs) into regional lymph nodes in WT mice. In Crth2(-/-) mice, its number was significantly smaller than that of WT mice. In conclusion, PGD(2)/CRTH2 signaling plays defensive role against second BV injection. This signaling promotes BV-specific IgE production at least partially by promoting DCs migration into regional lymph node.

肥大细胞（MC）的IgE依赖性/非依赖性激活被认为在皮肤抵御毒液注入方面起宿主防御作用。然而，其详细机制仍不清楚。我们旨在研究MC衍生的前列腺素D2（PGD(2)）介导的信号在宿主防御蜂毒（BV）中的作用。为此，我们利用了PGD(2)受体（即Th2细胞上表达的趋化因子受体同源分子（CRTH2））基因缺陷型小鼠。我们首先证实，皮下注射BV在野生型（WT）和CRTH2缺陷型（Crth2(-/-)）小鼠皮肤中产生的PGD(2)量相同。BV注射使两种小鼠的体温下降且肾脏受损情况相同。在野生型小鼠中，预先注射BV（3周）显著抑制了第二次BV注射引起的体温过低和肾脏损伤。相比之下，这种预先注射对Crth2(-/-)小鼠的第二次BV注射没有效果。我们还发现BV注射增加了野生型小鼠血清中BV特异性IgE水平，并且其血清输注到小鼠体内改善了未免疫野生型小鼠中BV诱导的体温过低。相反，Crth2(-/-)小鼠血清中BV特异性IgE水平显著较低。流式细胞术分析表明BV注射刺激树突状细胞（DCs）迁移到野生型小鼠的局部淋巴结。在Crth2(-/-)小鼠中，其数量明显少于野生型小鼠。总之，PGD(2)/CRTH2信号在抵御第二次BV注射中起防御作用。该信号至少部分通过促进DCs迁移到局部淋巴结来促进BV特异性IgE的产生。