CCR2 monocytes as therapeutic targets for acute disc herniation and radiculopathy in mouse models.

OBJECTIVE

Back pain and radiculopathy caused by disc herniation are major health issues worldwide. While macrophages are key players in disc herniation induced inflammation, their roles and origins in disease progression remain unclear. We aim to study the roles of monocytes and derivatives in a mouse model of disc herniation.

METHODS

Using a CCR2-CreER; R26R-EGFP (Ai6) transgenic mouse strain, we fate-mapped C-C chemokine receptor type 2 (CCR2) expressing monocytes and derivatives at disc herniation sites, and employed a CCR2 mouse strain and a CCR2-specific antagonist to study the effects of CCR2 monocytes on local inflammatory responses, pain level, and disc degeneration by immunostaining, flow cytometry, and histology.

RESULTS

CCR2 monocytes (GFP) increased at the sites of disc hernia over postoperative day 4, 6, and 9 in CCR2-CreER; Ai6 mice. F4/80 cells increased, and meanwhile, CD11b cells trended downward. Co-localization analysis revealed that both GFPCD11b and GFPF4/80 constituted the majority of CD11b and F4/80 cells at disc hernia sites. Fluorescence activated cell sorter purified GFP cells exhibited higher cytokine expressions than GFP cells. Inhibition of CCR2 signaling reduced infiltration of monocytes and macrophages, alleviated pain, maintained disc height, and reduced osteoclast activity in adjacent cortical bone for up to 1 month.

CONCLUSION

Our findings suggest that circulating CCR2 monocytes play important roles in initiating and promoting the local inflammatory responses, pain sensitization, and degenerative changes after disc herniation, and thus may serve as therapeutic targets for disc herniation induced back and leg pain.