The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity
The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity
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DOI：
10.1016/j.immuni.2015.08.010
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发表时间：
2015-09-15
期刊：
影响因子：
32.4
通讯作者：
Becher, Burkhard
中科院分区：
文献类型：
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作者：
Croxford, Andrew L.;Lanzinger, Margit;Becher, Burkhard
粒细胞-巨噬细胞集落刺激因子（GM-CSF）是由自身反应性辅助性T细胞（Th）产生的一种重要细胞因子，可引发组织炎症。多种类型的细胞可以感测GM-CSF，但致病性GM-CSF响应细胞的身份尚不清楚。通过使用条件基因靶向，我们系统地删除了整个髓系特定亚群中的GM-CSF受体（Csf 2 rb）。实验性自身免疫性脑脊髓炎（EAE）进展正常时，无论是经典的树突状细胞（cDC）或中性粒细胞缺乏GM-CSF的反应。Csf 2 rb缺失后，组织侵入单核细胞衍生的树突状细胞（moDCs）的发育也未受到干扰。相反，CCR 2（+）Ly 6C（hi）单核细胞中Csf 2 rb的缺失表型模仿了在完全Csf 2 rb缺陷小鼠中观察到的EAE抗性。组织浸润moDC的高维分析揭示了GM-CSF启动炎症机制的组合。这些结果表明，GM-CSF信号转导控制CCR 2（+）Ly 6C（hi）单核细胞及其后代中的致病性表达特征，这是组织损伤所必需的。
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine produced by auto-reactive T helper (Th) cells that initiate tissue inflammation. Multiple cell types can sense GM-CSF, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By using conditional gene targeting, we systematically deleted the GM-CSF receptor (Csf2rb) in specific subpopulations throughout the myeloid lineages. Experimental autoimmune encephalomyelitis (EAE) progressed normally when either classical dendritic cells (cDCs) or neutrophils lacked GM-CSF responsiveness. The development of tissue-invading monocyte-derived dendritic cells (moDCs) was also unperturbed upon Csf2rb deletion. Instead, deletion of Csf2rb in CCR2(+) Ly6C(hi) monocytes phenocopied the EAE resistance seen in complete Csf2rb-deficient mice. High-dimensional analysis of tissue-infiltrating moDCs revealed that GM-CSF initiates a combination of inflammatory mechanisms. These results indicate that GM-CSF signaling controls a pathogenic expression signature in CCR2(+)Ly6C(hi) monocytes and their progeny, which was essential for tissue damage.