Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Roche-Glycart, Schlieren, Switzerland.
Nat Immunol. 2022 Feb;23(2):217-228. doi: 10.1038/s41590-021-01117-7. Epub 2022 Jan 31.
During inflammation, Ly6C monocytes are rapidly mobilized from the bone marrow (BM) and are recruited into inflamed tissues, where they undergo monocyte-to-phagocyte transition (MTPT). The in vivo developmental trajectories of the MTPT and the contribution of individual cytokines to this process remain unclear. Here, we used a murine model of neuroinflammation to investigate how granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFNγ), two type 1 cytokines, controlled MTPT. Using genetic fate mapping, gene targeting and high-dimensional single-cell multiomics analyses, we found that IFNγ was essential for the gradual acquisition of a mature inflammatory phagocyte phenotype in Ly6C monocytes, while GM-CSF was required to license interleukin-1β (IL-1β) production, phagocytosis and oxidative burst. These results suggest that the proinflammatory cytokine environment guided MTPT trajectories in the inflamed central nervous system (CNS) and indicated that GM-CSF was the most prominent target for the disarming of monocyte progenies during neuroinflammation.
在炎症期间，Ly6C 单核细胞从骨髓 (BM) 中迅速动员，并招募到炎症组织中，在那里它们经历单核细胞向吞噬细胞的转变 (MTPT)。MTPT 的体内发育轨迹以及个别细胞因子对这一过程的贡献尚不清楚。在这里，我们使用神经炎症的小鼠模型来研究粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 和干扰素-γ (IFNγ) 这两种 I 型细胞因子如何控制 MTPT。通过遗传命运图谱、基因靶向和高维单细胞多组学分析，我们发现 IFNγ 对于 Ly6C 单核细胞中逐渐获得成熟的炎症性吞噬细胞表型是必不可少的，而 GM-CSF 则需要许可白细胞介素-1β (IL-1β) 的产生、吞噬作用和氧化爆发。这些结果表明，促炎细胞因子环境指导了炎症性中枢神经系统 (CNS) 中的 MTPT 轨迹，并表明 GM-CSF 是神经炎症期间消除单核细胞后代的最突出靶点。
