University of British Columbia, Biomedical Research Centre, Vancouver, British Columbia, Canada.
Nat Neurosci. 2011 Jul 31;14(9):1142-9. doi: 10.1038/nn.2887.
In multiple sclerosis and the experimental autoimmune encephalitis (EAE) mouse model, two pools of morphologically indistinguishable phagocytic cells, microglia and inflammatory macrophages, accrue from proliferating resident precursors and recruitment of blood-borne progenitors, respectively. Whether these cell types are functionally equivalent is hotly debated, but is challenging to address experimentally. Using a combination of parabiosis and myeloablation to replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor-dependent recruitment of monocytes to the CNS blocked EAE progression, suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that, although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, and therefore do not ultimately contribute to the resident microglial pool. In conclusion, we identified two distinct subsets of myelomonocytic cells with distinct roles in neuroinflammation and disease progression.
在多发性硬化症和实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中，两种形态上无法区分的吞噬细胞群——小胶质细胞和炎症性巨噬细胞——分别来自增殖的常驻前体细胞和血液来源的祖细胞的募集。这些细胞类型在功能上是否等效存在激烈的争论，但在实验上难以解决。我们使用联体共生和骨髓清除术来替代循环祖细胞，而不影响中枢神经系统常驻的小胶质细胞，发现单核细胞浸润与 EAE 进展至瘫痪阶段之间存在很强的相关性。抑制趋化因子受体依赖性单核细胞向中枢神经系统的募集可阻止 EAE 进展，表明这些浸润细胞对发病机制至关重要。最后，我们发现，尽管小胶质细胞可以进入细胞周期并在缓解后恢复静止，但募集的单核细胞消失，因此最终不会对常驻小胶质细胞池做出贡献。总之，我们确定了两种具有不同作用的骨髓单核细胞亚群，它们在神经炎症和疾病进展中具有不同的作用。
