中文摘要：

先天免疫是宿主防御的第一道防線，并參與疼痛的發生機制。然而，先天免疫系統如何與感覺神經元相互作用以調控疼痛，目前仍知之甚少。在此，我們報道白細胞介素33（IL-33）引發痛覺過敏，這一過程需要浸潤的巨噬細胞和中性粒細胞分泌趨化因子(C-C基序)配體2（CCL2），并激活感覺神經元中的瞬時受體電位香草酸1（TRPV1）和瞬時受體電位褪黑素8（TRPM8）通道。阻斷CCL2受體（CCR2）可減輕IL-33誘導的和弗氏佐劑（CFA）誘導的熱痛覺過敏；阻斷TRPV1和TRPM8則分別減輕IL-33誘導的機械性痛覺敏感性、熱覺敏感性以及冷痛覺異常。此外，巨噬細胞的耗竭（荷蘭Liposoma巨噬細胞清除劑）減少了IL-33誘導的疼痛、CCL2的表達及后爪皮膚中腫瘤發生抑制因子2（ST2）的抑制；抑制CCR2可防止巨噬細胞和中性粒細胞的招募。我們的發現揭示了一個未被認識的神經免疫串擾：浸潤免疫細胞中的IL-33-CCL2信號與感覺神經元中的TRPV1/TRPM8相互作用，共同促進疼痛狀態。

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.

論文信息：

論文題目：IL-33/ST2 drives inflammatory pain via CCL2 signaling and activation of TRPV1 and TRPM8

期刊名稱：Nature Communications

時間期卷：8, Article number: 724 (2025)

在線時間：2025年5月10日

DOI：doi.org/10.1038/s42003-025-08119-3

產品信息：

貨號：CP-005-005

規格：5ml+5ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點科技）

注射方式：腹腔注射

劑量和頻率：200ul/次，每天一次，連續注射兩次

氯膦酸鹽二鈉脂質體清除單核巨噬細胞，在疼痛模型中單核巨噬細胞功能研究，荷蘭Liposoma巨噬細胞清除劑Clodronate Liposomes見刊于Nature Communications：IL-33/ST2通過CCL2信號傳導和TRPV1及TRPM8的激活推動炎癥性疼痛

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

Drug treatment in pain models

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.