Acute systemic macrophage depletion in osteoarthritic mice alleviates pain-related behavior and does not affect joint damage

Background: Osteoarthritis (OA) is a painful degenerative joint disease and a leading cause of years of disability worldwide due to inadequate treatment options. Neuroimmune interactions are thought to contribute to the pathogenesis of OA pain. In rodents in particular, macrophages in the DRG are associated with the onset of persistent OA pain. Our aim was to determine the effects of acute systemic macrophage depletion on pain-related behavior and joint damage using surgical mouse models in both sexes. Methods: We depleted CSF1R+ macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8 or 16 weeks after medial meniscus destabilization (DMM) with AP20187 or vehicle control (10 mg/kg ip, 1x/day for 5 days), or by treating female MaFIA mice 12 weeks after partial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1-3 days before and after depletion, and 3-4 days after the last injection we examined joint histopathology and performed flow cytometry of dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we performed DRG bulk RNA sequencing analyses following 5 days of vehicle or AP20187 treatment. Results: Eight and 16 weeks after DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed relief of mechanical allodynia, knee hyperalgesia, and weight-bearing deficits following macrophage depletion 12 weeks after PMX. Macrophage depletion did not affect the extent of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG showed that macrophages and neutrophils were reduced following AP20187 treatment. Furthermore, in the DRG, only MHCII+ M1-like macrophages were significantly reduced, while CD163+MHCII- M2-like macrophages were unaffected in both sexes. DRG bulk RNA-seq showed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naïve mice, and were downregulated in DMM after acute macrophage depletion. Conclusions: Acute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insights into the regulation of immune cells in the DRG during OA.