Key role of CCR2-expressing macrophages in a mouse model of low back pain and radiculopathy

• Published in: Brain, behavior, and immunity Vol. 91; pp. 556 - 567
• Main Authors: Zhang, Li, Xie, Wenrui, Zhang, Jingdong, Shanahan, Hailey, Tonello, Raquel, Lee, Sang Hoon, Strong, Judith A., Berta, Temugin, Zhang, Jun-Ming
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2021
• Subjects: Animals; CCR2; Chemokine CCL2; Clodronate; Clodronic Acid; CX3CR1; Disease Models, Animal; Dorsal root ganglion; Ganglia, Spinal; INCB3344; Low Back Pain; Macrophage; Macrophages; MCP-1; Mice; Radicular pain; Radiculopathy; Receptors, CCR2 - genetics; CX3CR1; MCP-1; Radicular pain; Dorsal root ganglion; INCB3344; Clodronate; CCR2; Macrophage
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2020.11.015

•CCR2- and CX3CR1-expressing macrophage subsets may play distinct roles in pain.•Local DRG inflammation (a radiculopathy model) increased pain behaviors in mice.•DRG inflammation increased CCL2 and CCR2+ macrophages in the DRG.•Three methods of reducing CCR2+ macrophage infiltration reduced pain behaviors.•Genetically identifying macrophage subsets can elucidate macrophage roles in pain. 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.