Department of Biochemistry and Complex Traits Group, McGill University, Montreal, Quebec, Canada.
PLoS Pathog. 2013;9(7):e1003491. doi: 10.1371/journal.ppat.1003491. Epub 2013 Jul 11.
Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8(R294C)) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We report that BXH2 are completely resistant to the development of cerebral malaria (ECM) following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes increased by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes (including the Irf8 transcription partner Irf1) confers protection against ECM. ECM-resistance in Irf8 and Irf1 mutants is associated with impaired myeloid and lymphoid cells function, including production of IL12p40 and IFNγ. We note strong overlap between genes bound and regulated by IRF8 during ECM and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. We report a common core of IRF8-bound genes forming a critical inflammatory host-response network.
干扰素调节因子 8（IRF8）是髓系细胞发育、成熟和抗微生物防御表达所必需的。BXH2 小鼠在 Irf8（Irf8(R294C)）上携带有严重的功能缺失等位基因，导致其易感染包括结核分枝杆菌在内的细胞内病原体。我们报告称，BXH2 在感染伯氏疟原虫 ANKA 后完全抵抗脑型疟疾（ECM）的发展。对脑 RNA 的比较转录谱以及染色质免疫沉淀和高通量测序（ChIP-seq）的分析，用于鉴定与病理性急性神经炎症相关的 IRF8 调节基因。被感染增加的基因强烈富集 IRF8 结合位点，表明 IRF8 在炎症程序中作为转录激活物发挥作用。这些列表富含髓系特异性途径，包括干扰素反应、抗原呈递和 Th1 极化细胞因子。我们表明，失活这些下游靶基因中的几个（包括 Irf8 转录伙伴 Irf1）可赋予对 ECM 的保护作用。Irf8 和 Irf1 突变体的 ECM 抗性与髓样细胞和淋巴样细胞功能受损有关，包括 IL12p40 和 IFNγ 的产生。我们注意到，在 ECM 期间由 IRF8 结合和调节的基因与在结核分枝杆菌感染小鼠的肺部中调节的基因之间存在很强的重叠。这个由 IRF8 调控的网络包含了几个最近在急性和慢性人类炎症条件下被确定为风险因素的基因。我们报告了一个由 IRF8 结合基因组成的关键炎症宿主反应网络的共同核心。
