UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Curriculum, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Neuron. 2021 Apr 21;109(8):1274-1282.e6. doi: 10.1016/j.neuron.2021.02.018. Epub 2021 Mar 4.
Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1 spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1 spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.
外周神经损伤会引起脊髓胶质细胞的长期促炎反应，从而促进神经病理性疼痛，但尚未确定内源性细胞来解决脊髓炎症。通过单细胞 RNA 测序 (scRNA-seq)，我们发现，在轻度损伤（神经未损伤）后，MRC1 脊髓小胶质细胞会增殖并上调抗炎介质 CD163，但在神经损伤的动物中，这种反应会减弱。在轻度损伤动物中耗尽脊髓小胶质细胞会促进小胶质细胞增生，并导致机械性痛觉过敏持续存在。相反，在脊髓小胶质细胞中表达 CD163 会增加白细胞介素 10 的表达，减轻小胶质细胞和星形胶质细胞的增生，并持久缓解神经损伤动物的机械性和热敏感性。我们的数据表明，MRC1 脊髓小胶质细胞可积极抑制胶质细胞，从而限制轻度损伤后的神经炎症和机械性疼痛。此外，我们还表明，来自神经损伤动物的脊髓小胶质细胞会产生减弱的抗炎反应，但可以通过治疗来诱导其促进神经病理性疼痛的持久恢复。
