Chronic low back pain is a common condition, with high societal costs and often ineffectual treatments. Communication between macrophages/monocytes (MØ) and sensory neurons has been implicated in various preclinical pain models. However, few studies have examined specific MØ subsets, although distinct subtypes may play opposing roles. This study used a model of low back pain/radiculopathy involving direct local inflammation of the dorsal root ganglia (DRG). Reporter mice were employed that had distinct fluorescent labels for two key MØ subsets: CCR2-expressing (infiltrating pro-inflammatory) MØ, and CX3CR1-expressing (resident) macrophages. We observed that local DRG inflammation induced pain behaviors in mice, including guarding behavior and mechanical hypersensitivity, similar to the previously described rat model. The increase in MØ in the inflamed DRG was dominated by increases in CCR2+ MØ, which persisted for at least 14 days. The primary endogenous ligand for CCR2, CCL2, was upregulated in inflamed DRG. Three different experimental manipulations that reduced the CCR2+ MØ influx also reduced pain behaviors: global CCR2 knockout; systemic injection of INCB3344 (specific CCR2 blocker); and intravenous injection of liposomal clodronate. The latter two treatments when applied around the time of DRG inflammation reduced CCR2+ but not CX3CR1+ MØ in the DRG. Together these experiments suggest a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy. Intravenous clodronate given after pain was established had the opposite effect on pain behaviors, suggesting the role of macrophages or their susceptibility to clodronate may change with time.

中文翻译：

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表达 CCR2 的巨噬细胞在小鼠腰痛和神经根病模型中的关键作用


慢性腰痛是一种常见病，社会成本很高，而且治疗往往无效。巨噬细胞/单核细胞 (MØ) 和感觉神经元之间的通讯与各种临床前疼痛模型有关。然而，尽管不同的亚型可能发挥相反的作用，但很少有研究检查特定的 MØ 亚型。这项研究使用了腰痛/神经根病模型，涉及背根神经节（DRG）的直接局部炎症。使用的报告小鼠对两个关键 MØ 子集具有不同的荧光标记：表达 CCR2（浸润促炎）MØ 和表达 CX3CR1（常驻）巨噬细胞。我们观察到局部 DRG 炎症会诱发小鼠的疼痛行为，包括防御行为和机械超敏反应，类似于之前描述的大鼠模型。发炎的 DRG 中 MØ 的增加主要是 CCR2+ MØ 的增加，这种增加持续了至少 14 天。 CCR2 的主要内源配体 CCL2 在发炎的 DRG 中表达上调。减少 CCR2+ MØ 流入的三种不同实验操作也减少了疼痛行为：全局 CCR2 敲除；全身注射 INCB3344（特异性 CCR2 阻断剂）；以及静脉注射氯膦酸脂质体。后两种治疗在 DRG 炎症期间应用时，会减少 DRG 中的 CCR2+，但不会减少 CX3CR1+ MØ。这些实验共同表明，CCR2/CCL2 系统在炎症性腰痛和神经根病模型中建立疼痛状态方面发挥着关键作用。疼痛确立后静脉注射氯膦酸盐对疼痛行为产生相反的影响，表明巨噬细胞的作用或其对氯膦酸盐的敏感性可能随时间而变化。