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CCR2 monocytes as therapeutic targets for acute disc herniation and radiculopathy in mouse models
Li Jin1, Li Xiao1, Brock J Manley1
1Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA.
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 CCR2RFP/RFP 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 GFP+CD11b+ and GFP+F4/80+ 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.
Insights
Circulating monocytes expressing C-C chemokine receptor type 2 (CCR2) drive inflammation and degeneration after disc herniation. Targeting CCR2+ monocytes may alleviate pain and slow disease progression.
Area of Science:
- Immunology and Inflammation Research
- Musculoskeletal Disorders
- Pain Mechanisms
Background:
- Disc herniation causes significant back and leg pain globally.
- Macrophages are implicated in disc herniation inflammation, but their origins and roles are unclear.
- Understanding monocyte and derivative contributions is crucial for therapeutic development.
Purpose of the Study:
- To investigate the role of C-C chemokine receptor type 2 (CCR2) expressing monocytes and their derivatives in a mouse model of disc herniation.
- To elucidate the origins and functions of these cells at the site of disc herniation.
Main Methods:
- Utilized CCR2-CreER; R26R-EGFP transgenic mice for fate-mapping CCR2+ monocytes.
- Employed CCR2RFP/RFP mice and a CCR2 antagonist to assess CCR2+ monocyte effects.
- Analyzed inflammatory responses, pain, and disc degeneration using immunostaining, flow cytometry, and histology.
Main Results:
- CCR2+ monocytes (GFP+) significantly increased at disc herniation sites post-surgery.
- Inhibition of CCR2 signaling reduced monocyte/macrophage infiltration, alleviated pain, preserved disc height, and decreased osteoclast activity.
- CCR2+ monocytes exhibited higher pro-inflammatory cytokine expression compared to CCR2-negative cells.
Conclusions:
- Circulating CCR2+ monocytes are key drivers of inflammation, pain sensitization, and degeneration following disc herniation.
- These monocytes initiate and promote local inflammatory responses and degenerative changes.
- CCR2+ monocytes represent a promising therapeutic target for managing pain associated with disc herniation.
