中文摘要：

炎症诱导疼痛的机制已被广泛研究。然而，疼痛缓解的机制尚不充分清楚。本研究，由巨噬细胞（MΦs）而非小胶质细胞表达的GPR37有助于缓解炎症性疼痛。神经保护素D1（NPD1）和前体肽TX14增加了GPR37转染的HEK293细胞中的细胞内Ca2+（iCa2+）水平。NPD1和TX14也与GPR37结合，导致腹膜MΦs中GPR37依赖性iCa2+增加。NPD1和TX14激活GPR37通过钙信号触发酵母聚糖颗粒的MΦ吞噬。后爪注射pH敏感酵母聚糖颗粒不仅会引起炎性疼痛和中性粒细胞和MΦs的浸润，还会导致MΦs中GPR37的上调，炎症爪中MΦs对酵母聚糖颗粒和中性粒的吞噬作用，以及WT小鼠炎性疼痛的缓解。缺乏Gpr37的小鼠表现出MΦ吞噬活性的缺陷和炎症疼痛的延迟缓解。Gpr37缺陷型MΦs也表现出促炎和抗炎细胞因子的失调。氯膦酸盐脂质体（Liposoma）MΦ清除延迟炎性疼痛的消退。过继性转移WT而非Gpr37缺陷的MΦs可促进炎性疼痛的缓解。我们的研究结果揭示了GPR37在调节MΦ吞噬作用和炎性疼痛消退中以前未被认识的作用。

英文摘要：

The mechanisms of pain induction by inflammation have been extensively studied. However, the mechanisms of pain resolution are not fully understood. Here, we report that GPR37, expressed by macrophages (MΦs) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa2+) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa2+ increases in peritoneal MΦs. Activation of GPR37 by NPD1 and TX14 triggers MΦ phagocytosis of zymosan particles via calcium signaling. Hind paw injection of pH-sensitive zymosan particles not only induces inflammatory pain and infiltration of neutrophils and MΦs, but also causes GPR37 upregulation in MΦs, phagocytosis of zymosan particles and neutrophils by MΦs in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in MΦ phagocytic activity and delayed resolution of inflammatory pain. Gpr37-deficient MΦs also show dysregulations of proinflammatory and antiinflammatory cytokines. MΦ depletion（Liposoma） delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient MΦs promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating MΦ phagocytosis and inflammatory pain resolution.

论文信息：

论文题目： GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain

期刊名称：J Clin Invest.  

时间期卷：2018;128(8):3568–3582.

在线时间：2018年7月16日

DOI：doi.org/10.1172/JCI99888.

Clodronate Liposomes氯膦酸盐脂质体助力炎性疼痛模型巨噬细胞研究，Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JCI：

Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：

JCI期刊巨噬细胞清除解决方案

Given the important role of GRP37 in MΦ signaling, we examined the specific contribution of MΦs to zymosan-induced inflammatory pain using both loss-of-function (MΦ toxin) and gain-of-function (cell adoptive transfer) approaches. Depletion of MΦs via systemic injection of the MΦ toxin clodronate , administered 2 hours and 48 hours prior to the zymosan injection, largely reduced the number of MΦs in the inflamed skin . In contrast, the number of neutrophils was not affected by the toxin. Importantly, this MΦ depletion recapitulated the pain phenotypes observed in Gpr37−/− mice: the resolution, but not the induction, of inflammatory pain (heat hyperalgesia and mechanical allodynia) was impaired after the clodronate treatment .