CSF1R signaling is a regulator of pathogenesis in progressive MS.
CSF1R signaling is a regulator of pathogenesis in progressive MS.
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DOI：
10.1038/s41419-020-03084-7
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发表时间：
2020-10-23
影响因子：
9
通讯作者：
Ofengeim D
中科院分区：
文献类型：
--
作者：
Hagan N;Kane JL;Grover D;Woodworth L;Madore C;Saleh J;Sancho J;Liu J;Li Y;Proto J;Zelic M;Mahan A;Kothe M;Scholte AA;Fitzgerald M;Gisevius B;Haghikia A;Butovsky O;Ofengeim D
小胶质细胞作为中枢神经系统（CNS）的先天性免疫细胞，通过提供CNS微环境的持续监视和启动防御机制来保护CNS组织。损伤后，小胶质细胞转变为活化状态，改变其转录谱，改变其形态，并产生促炎细胞因子。这些激活的小胶质细胞最初起着有益的作用，但它们的持续激活会导致神经炎症和神经变性。多发性硬化（MS）是一种慢性、炎性、中枢神经系统脱髓鞘疾病，活化的小胶质细胞和巨噬细胞在介导疾病的病理生理和进展中起重要作用。集落刺激因子-1受体（CSF 1 R）及其配体CSF 1在MS患者的CNS组织中升高。我们进行了大规模的RNA测序实验，并确定CSF 1 R作为疾病进展的关键节点在小鼠模型进行性MS。我们假设，通过抑制CSF 1 R调节小胶质细胞和浸润性巨噬细胞将减弱有害的CNS炎症，并减少随后的脱髓鞘和神经变性。为了验证这一假设，我们产生了一种新的有效的和选择性的小分子CSF 1 R抑制剂（sCSF 1 Rinh）用于临床前测试。sCSF 1 Rinh阻断了小胶质细胞和巨噬细胞中的受体磷酸化和下游信号传导，并改变了细胞功能，包括增殖、存活和细胞因子产生。在体内，在小鼠急性LPS模型中，用sCSF 1 Rinh抑制CSF 1 R减轻了神经炎症并减少了小胶质细胞增殖。此外，sCSF 1 Rinh减弱了疾病相关的小胶质细胞表型，并在MS的实验性自身免疫性脑脊髓炎（EAE）模型中阻断了轴突损伤和神经损伤。虽然以前的研究集中在CSF 1 R抑制后的小胶质细胞耗竭，但我们的数据清楚地表明，该受体下游的信号传导可以在CNS损伤的背景下进行有益的调节。总之，这些数据表明，CSF 1 R抑制可以减少有害的小胶质细胞增殖，并在神经炎症发病机制中调节小胶质细胞表型，特别是在进行性MS中。
Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1Rinh) for preclinical testing. sCSF1Rinh blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. In vivo, CSF1R inhibition with sCSF1Rinh attenuated neuroinflammation and reduced microglial proliferation in a murine acute LPS model. Furthermore, the sCSF1Rinh attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.
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影响因子：
9.3
作者：
Borjini N;Fernández M;Giardino L;Calzà L
通讯作者：
Calzà L
影响因子：
64.8
作者：
Hubler Z;Allimuthu D;Bederman I;Elitt MS;Madhavan M;Allan KC;Shick HE;Garrison E;T Karl M;Factor DC;Nevin ZS;Sax JL;Thompson MA;Fedorov Y;Jin J;Wilson WK;Giera M;Bracher F;Miller RH;Tesar PJ;Adams DJ
通讯作者：
Adams DJ
影响因子：
64.5
作者：
Keren-Shaul, Hadas;Spinrad, Amit;Amit, Ido
通讯作者：
Amit, Ido
影响因子：
25
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Moore, Craig S.;Cialic, Ron;Lanser, Amanda J.;Gabriely, Galina;Koeglsperger, Thomas;Dake, Ben;Wu, Pauline M.;Doykan, Camille E.;Fanek, Zain;Liu, LiPing;Chen, Zhuoxun;Rothstein, Jeffrey D.;Ransohoffl, Richard M.;Gygi, Steven P.;Antel, Jack P.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
6.2
作者：
Gushchina, Svetlana;Pryce, Gareth;Bo, Xuenong
通讯作者：
Bo, Xuenong