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

Chronic low back pain is a common condition, with high societal costs and often ineffectual treatments. Communication between macrophages/monocytes (Mempty set) and sensory neurons has been implicated in various preclinical pain models. However, few studies have examined specific Mempty set 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 Mempty set subsets: CCR2-expressing (infiltrating pro-inflammatory) Mempty set, 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 MO in the inflamed DRG was dominated by increases in CCR2(+) Mempty set, 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(+) Mempty set influx also reduced pain behaviors: global CCR2 knockout; systemic injection of INCB3344 (specific CCR2 blocker); and intravenous injection of liposomal clodmnate. The latter two treatments when applied around the time of DRG inflammation reduced CCR2(+) but not CX3CR1(+) Mempty set 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.

Automated summary

Chronic low back pain is a common condition with high societal costs and often ineffective treatments. This study found that the CCR2/CCL2 system plays a key role in establishing the pain state in this model of inflammatory low back pain and radiculopathy, with different subsets of macrophages potentially influencing the pain state.