骨关节炎(OA)是一种疼痛的退行性关节疾病,并且是由于治疗选择不足而导致全球残疾的主要原因。据报道,神经免疫相互作用有助于OA疼痛的发病机理。值得注意的是,在啮齿动物中,DRG中的巨噬细胞与持续性OA疼痛的发作有关。我们的目的是使用两种性别的手术小鼠模型来确定急性全身巨噬细胞耗竭对疼痛相关行为和关节损伤的影响。
■我们通过在内侧半月板(DMM)失稳后8或16周处理雄性巨噬细胞Fas诱导的细胞凋亡(MaFIA)转基因小鼠,用AP20187或载体对照(10mg/kg腹膜内注射,1次/天,持续5天),或在部分半月板切除术(PMX)后12周用AP20187或媒介物对照治疗雌性MaFIA小鼠。我们测量了耗竭前后1-3天的疼痛相关行为,and,最后一次注射后3-4天,我们检查了关节组织病理学并进行了背根神经节(DRG)的流式细胞术。在一个单独的8周雄性DMM小鼠或年龄匹配的初始载体对照队列中,我们在5天载体或AP20187治疗后进行了DRG批量RNA测序分析.
■雄性小鼠DMM后8周和16周,AP20187诱导的巨噬细胞耗竭导致机械异常性疼痛和膝关节痛觉过敏减弱。雌性小鼠表现出机械异常性疼痛的缓解,膝关节痛觉过敏,以及PMX后12周巨噬细胞消耗后的负重缺陷。巨噬细胞耗竭不影响软骨退变的程度,骨赘宽度,或滑膜炎在任何性别。DRG的流式细胞术显示AP20187治疗后巨噬细胞和中性粒细胞减少。此外,在DRG中,只有MHCII+M1样巨噬细胞显著减少,而CD163+MHCII-M2样巨噬细胞在两性中均不受影响。DRG大量RNA-seq显示,与未接种小鼠相比,Cxcl10和Il1b在DMM手术中上调,并在急性巨噬细胞耗竭后在DMM中下调。
■急性全身性巨噬细胞耗竭降低了DRG中促炎巨噬细胞的水平,并减轻了男女小鼠手术诱导的OA的疼痛相关行为,不影响关节损伤。总的来说,这些研究提供了对OA期间DRG中免疫细胞调节的见解.
UNASSIGNED: Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes.
UNASSIGNED: We depleted CSF1R+ macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8- or 16-weeks post destabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kg i.p., 1x/day for 5 days), or treating female MaFIA mice 12 weeks post 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 the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment.
UNASSIGNED: Eight- and 16-weeks post DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weeks post PMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII+ M1-like macrophages were significantly decreased, while CD163+MHCII- M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naïve mice, and downregulated in DMM after acute macrophage depletion.
UNASSIGNED: 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 insight into immune cell regulation in the DRG during OA.