Acute microglia ablation induces neurodegeneration in the somatosensory system.
Acute microglia ablation induces neurodegeneration in the somatosensory system.
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DOI：
10.1038/s41467-018-05929-4
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发表时间：
2018-11-01
影响因子：
16.6
通讯作者：
Weiner HL
中科院分区：
文献类型：
--
作者：
Rubino SJ;Mayo L;Wimmer I;Siedler V;Brunner F;Hametner S;Madi A;Lanser A;Moreira T;Donnelly D;Cox L;Rezende RM;Butovsky O;Lassmann H;Weiner HL
先前的研究已经报道，小胶质细胞耗竭导致突触形成受损，并且这些细胞从CNS祖细胞迅速再生。然而，在CNS环境的长期状态下，小胶质细胞耗竭和再增殖的影响尚未得到表征。在这里，我们报告说，急性和同步的小胶质细胞耗竭和随后的再增殖诱导灰质小胶质细胞增生，神经元死亡的躯体感觉皮层和共济失调样行为。我们在小胶质细胞耗竭小鼠的退化躯体感觉皮层中发现了1型干扰素炎症特征。转录组学和大量细胞计数分析的重新填充小胶质细胞表明干扰素调节因子7驱动的激活状态。米诺环素和抗IFNAR1抗体治疗减弱CNS 1型干扰素驱动的炎症，恢复小胶质细胞稳态并减少共济失调行为。实验性自身免疫性脑脊髓炎期间小胶质细胞耗竭或再增殖均不影响神经病理学或T细胞反应。总之，我们发现急性小胶质细胞消融诱导与急性神经变性相关的灰质小胶质细胞的1型干扰素激活状态。先前的研究表明，在早期发育阶段小胶质细胞的耗竭导致神经元死亡。在这里，作者使用诱导系统消融成年期的小胶质细胞，表明这种消耗导致共济失调样行为和神经元损失，并确定可能起作用的炎症成分。
Previous studies have reported that microglia depletion leads to impairment of synapse formation and these cells rapidly repopulate from CNS progenitors. However, the impact of microglia depletion and repopulation in the long-term state of the CNS environment has not been characterized. Here, we report that acute and synchronous microglia depletion and subsequent repopulation induces gray matter microgliosis, neuronal death in the somatosensory cortex and ataxia-like behavior. We find a type 1 interferon inflammatory signature in degenerating somatosensory cortex from microglia-depleted mice. Transcriptomic and mass cytometry analysis of repopulated microglia demonstrates an interferon regulatory factor 7-driven activation state. Minocycline and anti-IFNAR1 antibody treatment attenuate the CNS type 1 interferon-driven inflammation, restore microglia homeostasis and reduce ataxic behavior. Neither microglia depletion nor repopulation impact neuropathology or T-cell responses during experimental autoimmune encephalomyelitis. Together, we found that acute microglia ablation induces a type 1 interferon activation state of gray matter microglia associated with acute neurodegeneration. Previous studies have shown that depletion of microglia at early developmental stages leads to neuronal death. Here the authors use an inducible system to ablate microglia in adulthood, showing that such depletion leads to ataxia-like behavior and neuronal loss, and identifying the inflammatory components that may contribute.
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影响因子：
11.2
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Cialic, Ron;Krasemann, Susanne;Murugaiyan, Gopal;Fanek, Zain;Greco, David J.;Wu, Pauline M.;Doykan, Camille E.;Kiner, Olga;Lawson, Robert J.;Frosch, Matthew P.;Pochet, Nathalie;El Fatimy, Rachid;Krichevsky, Anna M.;Gygi, Steven P.;Lassmann, Hans;Berry, James;Cudkowicz, Merit E.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
11.4
作者：
Cohen, Merav;Matcovitch, Orit;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
32.4
作者：
Croxford, Andrew L.;Lanzinger, Margit;Becher, Burkhard
通讯作者：
Becher, Burkhard
影响因子：
64.8
作者：
Bialas, Allison R.;Presumey, Jessy;Carroll, Michael C.
通讯作者：
Carroll, Michael C.