Microglial Inhibition as a Therapeutic Strategy for Subretinal Hemorrhage

我们正在继续研究视网膜下出血的小鼠模型，我们已经创建了该模型，以表征出血后急性发生的炎症反应和感光细胞变性。据观察，小胶质细胞浸润到视网膜外层早在出血后6小时开始。炎性细胞在感光细胞变性和凋亡的同时逐渐积聚在外核层中。米诺环素，一种小胶质细胞活化的抑制剂，在体外降低了小胶质细胞趋化细胞因子的表达，在体内视网膜下出血后减少了小胶质细胞浸润和感光细胞损失。 目前，我们正在使用这个模型来研究小胶质细胞与Muller细胞的通信，特别是TSPO介导的信号转导。 我们发现，在这个模型中的小胶质细胞活化伴随着TSPO的诱导表达。 视网膜中TSPO信号传导的诱导和作用揭示了协调的大胶质细胞-小胶质细胞相互作用的机制，其功能是限制炎症反应开始后的程度，促进恢复到基线静止。我们的研究结果表明，TSPO是一种有前途的分子标记物，用于成像视网膜中的炎性细胞活化，并强调DBI-TSPO信号传导作为免疫调节疗法的潜在靶点。

We are continuing working on a mouse model of subretinal hemorrhage that we have created to characterize the inflammatory responses and photoreceptor degeneration that occur in the acute aftermath of hemorrhage. It was observed that microglial infiltration into the outer retina commences as early as 6 hours after hemorrhage. Inflammatory cells progressively accumulate in the outer nuclear layer concurrently with photoreceptor degeneration and apoptosis. Administration of minocycline, an inhibitor of microglial activation, decreased microglial expression of chemotactic cytokines in vitro and reduced microglial infiltration and photoreceptor cell loss after subretinal hemorrhage in vivo. Currently, we are employing this model to examine microglial communications with Muller cells, particularly that underlying TSPO-mediated signaling. We found that microglial activation in this model is accompanied by the induced expression of TSPO. The inducibility and effects of TSPO signaling in the retina reveal a mechanism of coordinated macroglia-microglia interactions, the function of which is to limit the magnitude of inflammatory responses after their initiation, facilitating a return to baseline quiescence. Our results indicate that TSPO is a promising molecular marker for imaging inflammatory cell activation in the retina and highlight DBI-TSPO signaling as a potential target for immodulatory therapies.