Role of the Transcription Factor IRF-8 for Microglia Homeostasis and Function

到目前为止，人们只知道很少的因素可以调节小胶质细胞在非疾病条件下的静止。干扰素调节因子(IRF)-8对粒细胞、单核细胞、浆细胞样树突状细胞、CD8树突状细胞、骨髓源性巨噬细胞以及B细胞等髓系细胞的发育、成熟和扩增具有重要作用。值得注意的是，IRF-8突变最近也被描述为与整体先天免疫反应严重缺陷有关的人类。然而，关于IRF-8在原始造血的髓系细胞中的功能，尤其是脑内的小胶质细胞，目前还知之甚少。因此，我们将在这个项目中研究IRF-8在健康和疾病过程中对小胶质细胞功能的确切作用。在初步实验中，我们发现IRF-8缺乏深刻地改变了体内小胶质细胞的细胞结构和功能。因此，IRF-8的功能将在出生后小胶质细胞的发育和扩张过程中以及成年大脑的动态平衡期间进行检测。具体来说，我们打算破译IRF-8功能的分子途径和参与其中的相互作用伙伴。接下来，我们将研究IRF-8的转录调控，最后，我们将构建可诱导的小胶质细胞特异性IRF-8突变体，以描述IRF-8在中枢神经系统疾病中的功能。

Only few factors are known so far that regulate microglia quiescence under non-diseased conditions. Interferon regulatory factor (IRF)-8 has a well-known role for the development, maturation and expansion of myeloid cells such as granulocytes, monocytes, plasmacytoid and CD8+ dendritic cells and bone marrow-derived macrophages but also B cells. Notably, IRF-8 mutations were also recently described in humans associated with severe defects in overall innate immune responses. However, very few is known about the function of IRF-8 in myeloid cells of the primitive haematopoiesis, especially microglia in the brain. We will therefore investigate in this project the precise role of IRF-8 for microglia function during health and disease. In preliminary experiments we found that IRF-8 deficiency profoundly changed cellular architecture and function of microglia in vivo. Thus, IRF-8 function will be examined during development and expansion of microglia after birth as well as during homeostasis in the adult brain. In detail, we intend to decipher the molecular pathways of IRF-8 function and the interaction partners involved. Next, the regulation of IRF-8 transcription will be investigated and finally, we will generate inducible microglia-specific IRF-8 mutants to delineate the function of IRF-8 for CNS diseases.