Introduction:
Disc herniation is a leading cause of back and leg pain worldwide, often accompanied by heightened inflammation and macrophage presence at herniation sites. While the exact functions and origins of the immune cells remain unclear, C-C chemokine receptor 2 (CCR2), a monocyte-specific receptor, is known to mediate inflammatory cell migration. We hypothesize that CCR2-mediated monocyte infiltration at herniation sites leads to macrophage differentiation, driving inflammation and pain sensitization. This study investigates the impact of CCR2 blockade on inflammation, hyperalgesia, and structural integrity in disc herniation.
Methods:
We employed genetic and pharmacological approaches to block CCR2-dependent monocyte infiltration in a mouse model of disc herniation. CCR2-CreER; R26R-EGFP (Ai6) mice were used to fate-map monocytes and monocyte-derived macrophages through immunostaining, FACS, and RT-PCR. CCR2RFP/RFP mice and the CCR2 antagonist PF-4136309 further enabled analysis of monocyte effects on local inflammation, pain, and disc degeneration. Additionally, transient macrophage depletion was achieved using the MaFIA transgenic mouse model and AP20187 administration following annular puncture, with subsequent analyses of immune infiltration, neuroinflammation markers, and bone remodeling.
Results:
In CCR2-CreER; Ai6 mice, GFP+ monocytes infiltrated herniation sites peaked on postoperative day 6, with later co-localization of these cells with F4/80+ macrophages indicating monocyte differentiation. CCR2 depletion reduced monocyte and macrophage presence alleviated mechanical sensitivity, preserved disc height, and mitigated bone remodeling effects for up to four months post-injury. Pharmacologic CCR2 blockade produced similar outcomes. The MaFIA mouse model demonstrated that transient macrophage depletion altered the inflammatory cell landscape and osteoclast activity, preventing ectopic bone formation.
Conclusion:
These findings reveal a pivotal role of CCR2+ monocytes in driving inflammation, pain sensitization, and degenerative changes after disc herniation, supporting CCR2 as a potential target for managing both acute and chronic pain. The study also suggests that transient macrophage depletion can reduce structural degradation, highlighting a potential therapeutic strategy aimed at monocyte/macrophage infiltration to relieve disc herniation-associated pain and slow disease progression.