Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio 43210, USA.
J Neurosci. 2011 Jul 6;31(27):9910-22. doi: 10.1523/JNEUROSCI.2114-11.2011.
Macrophages exert divergent effects in the injured CNS, causing either neurotoxicity or regeneration. The mechanisms regulating these divergent functions are not understood but can be attributed to the recruitment of distinct macrophage subsets and the activation of specific intracellular signaling pathways. Here, we show that impaired signaling via the chemokine receptor CX3CR1 promotes recovery after traumatic spinal cord injury (SCI) in mice. Deficient CX3CR1 signaling in intraspinal microglia and monocyte-derived macrophages (MDMs) attenuates their ability to synthesize and release inflammatory cytokines and oxidative metabolites. Also, impaired CX3CR1 signaling abrogates the recruitment or maturation of MDMs with presumed neurotoxic effects after SCI. Indeed, in wild-type mice, Ly6C(lo)/iNOS(+)/MHCII(+)/CD11c(-) MDMs dominate the lesion site, whereas CCR2(+)/Ly6C(hi)/MHCII(-)/CD11c(+) monocytes predominate in the injured spinal cord of CX3CR1-deficient mice. Replacement of wild-type MDMs with those unable to signal via CX3CR1 resulted in anatomical and functional improvements after SCI. Thus, blockade of CX3CR1 signaling represents a selective anti-inflammatory therapy that is able to promote neuroprotection, in part by reducing inflammatory signaling in microglia and MDMs and recruitment of a novel monocyte subset.
巨噬细胞在受损的中枢神经系统中发挥不同的作用，导致神经毒性或再生。调节这些不同功能的机制尚不清楚，但可以归因于特定巨噬细胞亚群的募集和特定细胞内信号通路的激活。在这里，我们表明，趋化因子受体 CX3CR1 信号转导受损可促进小鼠创伤性脊髓损伤 (SCI) 后的恢复。脊髓内小胶质细胞和单核细胞衍生的巨噬细胞 (MDM) 中 CX3CR1 信号的缺陷减弱了它们合成和释放炎症细胞因子和氧化代谢物的能力。此外，CX3CR1 信号的缺陷消除了 SCI 后具有潜在神经毒性作用的 MDM 的募集或成熟。事实上，在野生型小鼠中，Ly6C(lo)/iNOS(+)/MHCII(+)/CD11c(-) MDM 占据病变部位，而 CCR2(+)/Ly6C(hi)/MHCII(-)/CD11c(+) 单核细胞在 CX3CR1 缺陷型小鼠的损伤脊髓中占优势。用不能通过 CX3CR1 信号转导的野生型 MDM 替代后，SCI 后的解剖和功能均得到改善。因此，阻断 CX3CR1 信号转导代表一种选择性抗炎治疗，可通过减少小胶质细胞和 MDM 中的炎症信号转导以及募集新型单核细胞亚群来促进神经保护。
