中文摘要：

炎癥誘導(dǎo)疼痛的機制已被廣泛研究。然而，疼痛緩解的機制尚不充分清楚。本研究，由巨噬細胞（MΦs）而非小膠質(zhì)細胞表達的GPR37有助于緩解炎癥性疼痛。神經(jīng)保護素D1（NPD1）和前體肽TX14增加了GPR37轉(zhuǎn)染的HEK293細胞中的細胞內(nèi)Ca2+（iCa2+）水平。NPD1和TX14也與GPR37結(jié)合，導(dǎo)致腹膜MΦs中GPR37依賴性iCa2+增加。NPD1和TX14激活GPR37通過鈣信號觸發(fā)酵母聚糖顆粒的MΦ吞噬。后爪注射pH敏感酵母聚糖顆粒不僅會引起炎性疼痛和中性粒細胞和MΦs的浸潤，還會導(dǎo)致MΦs中GPR37的上調(diào)，炎癥爪中MΦs對酵母聚糖顆粒和中性粒的吞噬作用，以及WT小鼠炎性疼痛的緩解。缺乏Gpr37的小鼠表現(xiàn)出MΦ吞噬活性的缺陷和炎癥疼痛的延遲緩解。Gpr37缺陷型MΦs也表現(xiàn)出促炎和抗炎細胞因子的失調(diào)。氯膦酸鹽脂質(zhì)體（Liposoma）MΦ清除延遲炎性疼痛的消退。過繼性轉(zhuǎn)移WT而非Gpr37缺陷的MΦs可促進炎性疼痛的緩解。我們的研究結(jié)果揭示了GPR37在調(diào)節(jié)MΦ吞噬作用和炎性疼痛消退中以前未被認識的作用。

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.

論文信息：

論文題目： GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain

期刊名稱：J Clin Invest.  

時間期卷：2018;128(8):3568–3582.

在線時間：2018年7月16日

DOI：doi.org/10.1172/JCI99888.

Clodronate Liposomes氯膦酸鹽脂質(zhì)體助力炎性疼痛模型巨噬細胞研究，Liposoma巨噬細胞清除劑Clodronate Liposomes見刊于JCI：

Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

JCI期刊巨噬細胞清除解決方案

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 .