中文摘要：
先天免疫是宿主防御的第一道防线，并参与疼痛的发生机制。然而，先天免疫系统如何与感觉神经元相互作用以调控疼痛，目前仍知之甚少。在此，我们报道白细胞介素33（IL-33）引发痛觉过敏，这一过程需要浸润的巨噬细胞和中性粒细胞分泌趋化因子(C-C基序)配体2（CCL2），并激活感觉神经元中的瞬时受体电位香草酸1（TRPV1）和瞬时受体电位褪黑素8（TRPM8）通道。阻断CCL2受体（CCR2）可减轻IL-33诱导的和弗氏佐剂（CFA）诱导的热痛觉过敏；阻断TRPV1和TRPM8则分别减轻IL-33诱导的机械性痛觉敏感性、热觉敏感性以及冷痛觉异常。此外，巨噬细胞的耗竭（荷兰Liposoma巨噬细胞清除剂）减少了IL-33诱导的疼痛、CCL2的表达及后爪皮肤中肿瘤发生抑制因子2（ST2）的抑制；抑制CCR2可防止巨噬细胞和中性粒细胞的招募。我们的发现揭示了一个未被认识的神经免疫串扰：浸润免疫细胞中的IL-33-CCL2信号与感觉神经元中的TRPV1/TRPM8相互作用，共同促进疼痛状态。
英文摘要：
Innate immunity is the first line of host defense and contributes to pain. However, how innate immune system interacts with sensory neurons to govern pain remains poorly understood. Here, we report that interleukin 33(IL-33) initiates pain hypersensitivity that requires chemokine (C-C motif) ligand 2 (CCL2) secretion from infiltrated macrophages and neutrophils and activation of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential melastatin 8 (TRPM8) channels in sensory neurons. Blocking CCL2 receptor (CCR2) attenuates IL-33- induced and Complete Freund’s adjuvant (CFA)-induced thermal hyperalgesia and blocking TRPV1 and TRPM8 attenuates IL-33-induced mechanical and thermal hypersensitivity and cold allodynia respectively. Furthermore, depletion of macrophages reduces IL-33-induced pain and expression of CCL2 and suppression of tumorigenicity 2 (ST2) in hindpaw skin and inhibition of CCR2 prevents recruitment of macrophages and neutrophils. Our findings reveal an unrecognized neuroimmune crosstalk of IL-33-CCL2 signaling from infiltrated immune cells with TRPV1/TRPM8 in sensory neurons to facilitate pain states.
论文信息：
论文题目：IL-33/ST2 drives inflammatory pain via CCL2 signaling and activation of TRPV1 and TRPM8
期刊名称：Nature Communications
时间期卷：8, Article number: 724 (2025)
在线时间：2025年5月10日
DOI：doi.org/10.1038/s42003-025-08119-3
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes and Control Liposomes
办事处：Target Technology（靶点科技）
注射方式：腹腔注射
剂量和频率：200ul/次，每天一次，连续注射两次
氯膦酸盐二钠脂质体清除单核巨噬细胞，在疼痛模型中单核巨噬细胞功能研究，荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：IL-33/ST2通过CCL2信号传导和TRPV1及TRPM8的激活推动炎症性疼痛
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
In the pre-treatment study, ST2 neutralizing antibody (0.5 μg/10 μL, MAB10041, R&D), CCR2 antagonist (INCB3344, 0.5 μg/10 μL, Apebio) or PBS was intraplanatarly delivered 30 min before IL-33 injection. Then mechanical PWT or thermal PWL was measured at 1, 2, and 4 h after IL-33 injection. For the post-treatment study, CFA model was set up and INCB3344 was intraplantarly injected at day 3 after CFA injection, then PWL was measured. For the macrophage depletion experiment, clondronate (200 μL, CP-005-005, Liposoma) was intraperitoneal injected once a day for two days, then IL-33 was intraplantarly injected. PWT and PWL were measured at 1, 2, and 4 h after IL-33 application.
