An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE.
An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE.
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DOI：
10.1186/s12974-018-1237-y
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发表时间：
2018-07-16
影响因子：
9.3
通讯作者：
Segal BM
中科院分区：
文献类型：
--
作者：
Stoolman JS;Duncker PC;Huber AK;Giles DA;Washnock-Schmid JM;Soulika AM;Segal BM
在C57 BL/6野生型（WT）宿主中，髓鞘少突胶质细胞糖蛋白（MOG）反应性辅助性T细胞（Th）1诱导传统的实验性自身免疫性脑脊髓炎（cEAE），其特征在于上行性麻痹和单核细胞占主导地位的脊髓浸润。在同基因IFNγ受体（IFNγR）缺陷型宿主中，相同的T细胞诱导非典型形式的EAE（aEAE），其特征为共济失调和嗜中性粒细胞为主的脑干浸润。CNS内ELR+ CXC趋化因子的产生是aEAE而非cEAE发展所必需的。CNS中ELR+ CXC趋化因子的细胞来源和定位以及调节其产生的IFNγ依赖性途径仍有待阐明。通过免疫组织化学和/或原位杂交确定ELR+ CXC趋化因子CXCL 1和CXCL 2的炎性病变和CNS表达的空间分布。通过流式细胞术和定量PCR（qPCR）分析测量白细胞亚群中/上的CXCL 1和CXCL 2及其同源受体CXCR 2的水平。在通过qPCR或流式细胞术测量CXCL 2和CXCR 2之前，将骨髓嗜中性粒细胞和巨噬细胞与炎性刺激物一起体外培养。CNS浸润性中性粒细胞和单核细胞以及常驻小胶质细胞是aEAE期间IFNγRKO过继转移受体脑干中CXCL 2的主要来源。在WT转移受体中，IFNγ直接抑制小胶质细胞和髓样细胞中的CXCL 2转录，以及CNS浸润中性粒细胞中的CXCR 2转录。因此，在cEAE期间，来自相邻脑膜的脑干实质的浸润被阻断。CXCL 2直接刺激其自身在培养的中性粒细胞中的表达，其被IL-1增强并被IFNγ抑制。我们提供了IFNγ调节的先天免疫细胞中CXCR 2/CXCL 2自分泌/旁分泌反馈环的证据，该反馈环决定了Th 1介导的EAE期间CNS浸润的位置。当IFNγ信号传导受损时，髓样细胞产生的CXCL 2增加，这促进脑干炎症并导致临床共济失调。WT受体CNS内产生的IFNγ抑制髓样细胞CXCR 2和CXCL 2的产生，从而使神经炎性浸润的位置偏向脊髓，并使临床表型偏向上行性麻痹。这些数据揭示了一种新的机制，IFNγ和CXCL 2相互作用，直接在中枢神经系统中的白细胞的区域募集，导致不同的临床表现。本文的在线版本（10.1186/s12974-018-1237-y）包含补充材料，可供授权用户使用。
Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated. The spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry. CNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ. We provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations. The online version of this article (10.1186/s12974-018-1237-y) contains supplementary material, which is available to authorized users.
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影响因子：
16.8
作者：
Hanamsagar R;Hanke ML;Kielian T
通讯作者：
Kielian T
DOI：
10.4049/jimmunol.1501097
发表时间：
2015-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Carbajal KS;Mironova Y;Ulrich-Lewis JT;Kulkarni D;Grifka-Walk HM;Huber AK;Shrager P;Giger RJ;Segal BM
通讯作者：
Segal BM
影响因子：
30.5
作者：
Reboldi, Andrea;Coisne, Caroline;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
14.5
作者：
Thorpe, JW;Kidd, D;Miller, DH
通讯作者：
Miller, DH
影响因子：
2.3
作者：
Wang, Xisheng;Michie, Sara A.;Suzuki, Yasuhiro
通讯作者：
Suzuki, Yasuhiro