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

到目前为止，只有很少的因素是已知的，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对骨髓细胞（如粒细胞、单核细胞、浆细胞样和CD 8+树突细胞和骨髓源性巨噬细胞以及B细胞）的发育、成熟和扩增具有众所周知的作用。值得注意的是，IRF-8突变最近在人类中也被描述为与整体先天免疫应答的严重缺陷相关。然而，很少有人知道IRF-8在原始造血的髓样细胞，特别是脑中的小胶质细胞中的功能。因此，我们将在这个项目中研究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缺陷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功能将在出生后小胶质细胞的发育和扩增期间以及在成人大脑中的稳态期间进行检查。详细地说，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，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对CNS疾病的功能。

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.