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

到目前为止，只有少数几个因素知道在非疾病条件下调节小胶质细胞的静止。干扰素调节因子(IRF)-8在骨髓细胞如粒细胞、单核细胞、浆细胞样细胞和CD8+树突状细胞、骨髓源性巨噬细胞以及B细胞的发育、成熟和扩增中发挥着众所周知的作用。值得注意的是，IRF-8突变最近也在人类中被描述为与整体先天免疫反应的严重缺陷相关。然而，关于IRF-8在原始造血髓系细胞，特别是脑小胶质细胞中的功能知之甚少。因此，我们将在本项目中研究IRF-8在健康和疾病期间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以及成年大脑的稳态过程中进行检查。详细来说，我们打算破译IRF-8功能的分子途径和所涉及的相互作用伙伴。接下来，我们将研究IRF-8转录的调控，最后，我们将产生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.