Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells.
Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells.
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DOI：
10.1016/j.bbi.2023.02.007
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发表时间：
2023-05
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神经祖细胞不表达IL-6顺式信号传导所需的机制，但小胶质细胞表达。急性IL-6诱导神经祖细胞和小胶质细胞的细胞特异性反应。小胶质细胞IL-6转录组与精神分裂症死后基因组重叠小胶质细胞-NPC共培养模型需要研究IL-6对神经发育的影响。产前暴露于升高的白细胞介素（IL）-6水平与具有假定的神经发育起源的精神疾病（如精神分裂症（SZ）、自闭症谱系障碍（ASC）和双相情感障碍（BD））的风险增加相关。尽管啮齿动物模型提供了这种关联的因果证据，但我们缺乏对人类模型系统中细胞和分子机制的详细了解。为了缩小这一差距，我们表征了人诱导多能干细胞（hiPSC-）衍生的小胶质细胞样细胞（MGL）和神经祖细胞（NPC）对单培养中IL-6的反应。我们观察到，由于缺乏IL 6 R表达和可溶性IL 6 Ra分泌，人前脑NPC在蛋白质和转录水平上对单一培养中的急性IL-6暴露没有反应。相比之下，急性IL-6暴露导致STAT 3磷酸化并增加MGL中的IL 6、JMJD 3和IL 10表达，证实了经典IL 6 Ra信号传导的激活。批量RNAseq鉴定了急性IL-6暴露后MGL中的156个上调基因（FDR < 0.05），包括IRF 8、REL、HSPA 1A/B和OXTR，其与来自精神分裂症个体的人死后脑组织的上调基因集显著重叠。急性IL-6刺激显著增加了MGL运动性，这与RNAseq数据中突出显示的基因本体论途径一致，并复制了IRF 8调节小胶质细胞运动性的啮齿动物模型指示。IL-6诱导MGL分泌CCL 1、CXCL 1、MIP-1α/β、IL-8、IL-13、IL-16、IL-18、MIF和Serpin-E1。我们的数据提供了在人类模型系统中急性IL-6暴露的细胞特异性效应的证据，最终表明需要小胶质细胞-NPC共培养模型来研究IL-6如何影响体外人皮质神经祖细胞发育。
Neural progenitor cells do not express required machinery for IL-6 cis-signaling but microglia do. Acute IL-6 induces cell specific responses from neural progenitor and microglia cells. Microglia IL-6 transcriptome overlaps with schizophrenia post-mortem genesets. Microglia-NPC co-culture models are required to investigate the IL-6 effect on neurodevelopment. Prenatal exposure to elevated interleukin (IL)-6 levels is associated with increased risk for psychiatric disorders with a putative neurodevelopmental origin, such as schizophrenia (SZ), autism spectrum condition (ASC) and bipolar disorder (BD). Although rodent models provide causal evidence for this association, we lack a detailed understanding of the cellular and molecular mechanisms in human model systems. To close this gap, we characterized the response of human induced pluripotent stem cell (hiPSC-)derived microglia-like cells (MGL) and neural progenitor cells (NPCs) to IL-6 in monoculture. We observed that human forebrain NPCs did not respond to acute IL-6 exposure in monoculture at both protein and transcript levels due to the absence of IL6R expression and soluble (s)IL6Ra secretion. By contrast, acute IL-6 exposure resulted in STAT3 phosphorylation and increased IL6, JMJD3 and IL10 expression in MGL, confirming activation of canonical IL6Ra signaling. Bulk RNAseq identified 156 up-regulated genes (FDR < 0.05) in MGL following acute IL-6 exposure, including IRF8, REL, HSPA1A/B and OXTR, which significantly overlapped with an up-regulated gene set from human post-mortem brain tissue from individuals with schizophrenia. Acute IL-6 stimulation significantly increased MGL motility, consistent with gene ontology pathways highlighted from the RNAseq data and replicating rodent model indications that IRF8 regulates microglial motility. Finally, IL-6 induces MGLs to secrete CCL1, CXCL1, MIP-1α/β, IL-8, IL-13, IL-16, IL-18, MIF and Serpin-E1 after 3 h and 24 h. Our data provide evidence for cell specific effects of acute IL-6 exposure in a human model system, ultimately suggesting that microglia-NPC co-culture models are required to study how IL-6 influences human cortical neural progenitor cell development in vitro.
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影响因子：
25
作者：
Galatro, Thais F.;Holtman, Inge R.;Eggen, Bart J. L.
通讯作者：
Eggen, Bart J. L.
影响因子：
8.8
作者：
Garcia-Reitboeck P;Phillips A;Piers TM;Villegas-Llerena C;Butler M;Mallach A;Rodrigues C;Arber CE;Heslegrave A;Zetterberg H;Neumann H;Neame S;Houlden H;Hardy J;Pocock JM
通讯作者：
Pocock JM
DOI：
10.1016/j.bbi.2022.06.010
发表时间：
2022-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
通讯作者：
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自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
DOI：
10.1126/science.aag3194
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Estes ML;McAllister AK
通讯作者：
McAllister AK