Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
Department of Rheumatology and Clinical Immunology, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
J Neurosci. 2021 Sep 29;41(39):8249-8261. doi: 10.1523/JNEUROSCI.1787-20.2021. Epub 2021 Aug 16.
Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Na1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain. In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.
疼痛是骨关节炎（OA）的主要致残症状，难以治疗。OA 患者的关节组织损伤与疼痛相关性差，表明其他机制也与 OA 疼痛有关。免疫细胞调节感觉系统，但对免疫细胞在 OA 疼痛中的参与知之甚少。在这里，我们报告在两种 OA 啮齿动物模型中，巨噬细胞在远离损伤部位的背根神经节（DRG）中积累。DRG 巨噬细胞获得了 M1 样表型，并且耗尽 DRG 巨噬细胞可缓解雄性和雌性小鼠的 OA 疼痛。损伤膝关节支配的感觉神经元将 DRG 巨噬细胞塑造成 M1 样表型。持续的 OA 疼痛、DRG 巨噬细胞的积累以及 DRG 巨噬细胞向 M1 样表型的编程都独立于 Na1.8 伤害感受器。鞘内注射 IL4-IL10 融合蛋白或 M2 样巨噬细胞抑制 DRG 中的 M1 样巨噬细胞可缓解持续性 OA 疼痛。总之，这些发现揭示了巨噬细胞在维持 OA 疼痛中的关键作用，这种作用独立于关节损伤，为治疗 OA 疼痛提供了一个新的方向。在 OA 患者中，疼痛与关节组织变化相关性差，表明除了组织损伤之外，还有其他机制会导致 OA 疼痛。我们发现，DRG 中含有感觉神经元的感觉神经元轴突的感觉神经元，这些神经元被感觉神经元塑造成 M1 样表型。我们表明，这些 DRG 巨噬细胞主动地、远程地维持 OA 疼痛，与关节损伤无关。这些巨噬细胞的表型对于促进疼痛的作用至关重要。用 M2 样巨噬细胞或使巨噬细胞向 M2 样表型倾斜的细胞因子融合蛋白靶向 DRG 巨噬细胞表型可缓解 OA 疼痛。我们的工作揭示了一种有助于维持远离受影响膝关节的 OA 疼痛的机制，并表明背根神经节巨噬细胞是治疗骨关节炎慢性疼痛的靶点。
