Department of Biochemistry, McGill University, Montréal, Canada.
PLoS Genet. 2011 Jun;7(6):e1002097. doi: 10.1371/journal.pgen.1002097. Epub 2011 Jun 23.
IRF8 (Interferon Regulatory Factor 8) plays an important role in defenses against intracellular pathogens, including several aspects of myeloid cells function. It is required for ontogeny and maturation of macrophages and dendritic cells, for activation of anti-microbial defenses, and for production of the Th1-polarizing cytokine interleukin-12 (IL-12) in response to interferon gamma (IFNγ) and protection against infection with Mycobacterium tuberculosis. The transcriptional programs and cellular pathways that are regulated by IRF8 in response to IFNγ and that are important for defenses against M. tuberculosis are poorly understood. These were investigated by transcript profiling and chromatin immunoprecipitation on microarrays (ChIP-chip). Studies in primary macrophages identified 368 genes that are regulated by IRF8 in response to IFNγ/CpG and that behave as stably segregating expression signatures (eQTLs) in F2 mice fixed for a wild-type or mutant allele at IRF8. A total of 319 IRF8 binding sites were identified on promoters genome-wide (ChIP-chip) in macrophages treated with IFNγ/CpG, defining a functional G/AGAAnTGAAA motif. An analysis of the genes bearing a functional IRF8 binding site, and showing regulation by IFNγ/CpG in macrophages and/or in M. tuberculosis-infected lungs, revealed a striking enrichment for the pathways of antigen processing and presentation, including multiple structural and enzymatic components of the Class I and Class II MHC (major histocompatibility complex) antigen presentation machinery. Also significantly enriched as IRF8 targets are the group of endomembrane- and phagosome-associated small GTPases of the IRG (immunity-related GTPases) and GBP (guanylate binding proteins) families. These results identify IRF8 as a key regulator of early response pathways in myeloid cells, including phagosome maturation, antigen processing, and antigen presentation by myeloid cells.
IRF8（干扰素调节因子 8）在抵抗细胞内病原体的防御中发挥着重要作用，包括骨髓细胞功能的多个方面。它是巨噬细胞和树突状细胞的个体发生和成熟所必需的，是激活抗微生物防御所必需的，并且是在干扰素γ（IFNγ）的刺激下产生 Th1 极化细胞因子白细胞介素-12（IL-12）以及对结核分枝杆菌（Mycobacterium tuberculosis）感染的保护所必需的。IRF8 响应 IFNγ 调节的转录程序和细胞途径，以及对结核分枝杆菌防御至关重要的途径，目前了解甚少。通过微阵列（ChIP-chip）上的转录谱和染色质免疫沉淀研究了这些途径。对原代巨噬细胞的研究确定了 368 个基因，这些基因受 IRF8 响应 IFNγ/CpG 的调节，并且在固定 IRF8 野生型或突变等位基因的 F2 小鼠中表现为稳定分离的表达特征（eQTLs）。在 IFNγ/CpG 处理的巨噬细胞中，在全基因组范围内（ChIP-chip）鉴定出 319 个 IRF8 结合位点，定义了一个功能性 G/AGAAnTGAAA 基序。对具有功能性 IRF8 结合位点的基因进行分析，并在巨噬细胞和/或结核分枝杆菌感染的肺中观察到 IFNγ/CpG 的调节，发现抗原加工和呈递途径显著富集，包括 I 类和 II 类 MHC（主要组织相容性复合体）抗原呈递机制的多个结构和酶成分。作为 IRF8 靶标的还有显著富集的是内体膜和吞噬体相关的小 GTPases 家族的免疫相关 GTPases（IRG）和鸟嘌呤核苷酸结合蛋白（GBP）家族。这些结果表明，IRF8 是骨髓细胞中早期反应途径的关键调节剂，包括吞噬体成熟、抗原加工和抗原呈递。
