The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, MD, USA.
Neuron. 2019 Feb 6;101(3):412-420.e3. doi: 10.1016/j.neuron.2019.01.012. Epub 2019 Jan 24.
Mast cells can be found in close proximity to peripheral nerve endings where, upon activation, they release a broad range of pro-inflammatory cytokines and chemokines. However, the precise mechanism underlying this so-called neurogenic inflammation and associated pain has remained elusive. Here we report that the mast-cell-specific receptor Mrgprb2 mediates inflammatory mechanical and thermal hyperalgesia and is required for recruitment of innate immune cells at the injury site. We also found that the neuropeptide substance P (SP), an endogenous agonist of Mrgprb2, facilitates immune cells' migration via Mrgprb2. Furthermore, SP activation of the human mast cell led to the release of multiple pro-inflammatory cytokines and chemokines via the human homolog MRGPRX2. Surprisingly, the SP-mediated inflammatory responses were independent of its canonical receptor, neurokinin-1 receptor (NK-1R). These results identify Mrgprb2/X2 as an important neuroimmune modulator and a potential target for treating inflammatory pain.
肥大细胞可以在周围神经末梢附近被发现，在那里，它们在被激活后会释放出广泛的促炎细胞因子和趋化因子。然而，这种所谓的神经源性炎症和相关疼痛的确切机制仍然难以捉摸。在这里，我们报告说，肥大细胞特异性受体 Mrgprb2 介导炎症性机械和热痛觉过敏，并且是在损伤部位募集先天免疫细胞所必需的。我们还发现，神经肽物质 P（SP），Mrgprb2 的内源性激动剂，通过 Mrgprb2 促进免疫细胞的迁移。此外，SP 激活人肥大细胞会通过人同源物 MRGPRX2 释放多种促炎细胞因子和趋化因子。令人惊讶的是，SP 介导的炎症反应独立于其经典受体，神经激肽-1 受体（NK-1R）。这些结果确定 Mrgprb2/X2 是一种重要的神经免疫调节剂，也是治疗炎症性疼痛的潜在靶点。
