Control of Local CNS Inflammation

项目总结 多发性硬化症(MS)是一种中枢神经系统(CNS)的自身免疫性疾病， 这是导致年轻人神经功能障碍的主要原因。星形胶质细胞在多发性硬化及其模型中起着重要作用， 实验性自身免疫性脑脊髓炎(EAE)，但对星形胶质细胞活性的调节较差 明白了。星形胶质细胞调控的研究有望确定其发病机制和治疗方法。 多发性硬化症的靶点，特别是在没有有效治疗方法的二次进展期。 我们发现了一条由配体激活的转录因子芳香烃受体控制的途径。 (AHR)在炎症过程中调节星形胶质细胞的功能。简而言之，星形胶质细胞中的AhR促进了该基因的表达 细胞因子信号转导抑制因子2(SOCS2)，一种核转录因子κB激活的抑制因子。星形胶质细胞中的AHR缺失 上调NF-κB活性，加重EAE。这些数据表明AhR/SOCS2信号通路抑制了 星形胶质细胞通过限制NF-κB的激活在EAE中的致病活性。为了支持这一解释，鼻音 给予AhR激动剂ITE通过AhR介导的机制抑制星形胶质细胞的EAE。 此外，来自饮食色氨酸(Trp)和肠道菌群的激动剂通过AhR改善EAE。 星形胶质细胞。这些AhR激动剂在MS患者中减少，表明AhR激活不足 与疾病的发病机制有关。总的来说，这些发现确定了一种新的AhR/SOCS2途径 整合内源性和环境信号来控制星形胶质细胞的功能。我们假设AhR在 星形胶质细胞限制中枢神经系统炎症，是多发性硬化症的潜在治疗靶点。我们的具体目标是： 具体目标1：AHR是否抑制EAE期间星形胶质细胞驱动的神经毒性？ 我们建议：1)确定星形胶质细胞AhR在EAE过程中对神经毒性的影响；2)建立 SOCS2对NF-κB活化和星形胶质细胞神经毒性的影响，3)确定AhR是否限制了NF-κB- SOCS2引起的星形胶质细胞神经毒性。 特定目的2：AHR如何控制星形胶质细胞的转录程序？ 我们建议：1)确定AhR在控制星形胶质细胞转录反应中的作用 EAE，2)确定SOCS2在星形胶质细胞AhR转录效应中的作用，3)建立 单细胞RNA序列分析EAE过程中星形胶质细胞反应的异质性及其AhR的调控。 特定目标3：AHR是调节星形胶质细胞功能的治疗靶点吗？ 我们建议：1)评估ITE激活AhR对星形胶质细胞和中枢神经系统炎症的影响 鼻腔给药，2)确定AhR/SOCS2在慢性进行性结节EAE星形胶质细胞中的作用， 3)评价鼻腔ITE对NOD EAE的治疗价值。 总之，本项目使用独特的实验系统来研究新型AhR/SOCS2的作用 星形胶质细胞在中枢神经系统炎症中的通路及其作为治疗靶点的潜力。

PROJECT SUMMARY Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that constitutes the leading cause of neurologic disability in young adults. Astrocytes play important roles in MS and its model, experimental autoimmune encephalomyelitis (EAE), but the regulation of astrocyte activity is poorly understood. The study of astrocyte regulation is likely to identify mechanisms of pathogenesis and therapeutic targets in MS, particularly for its secondary progressive phase for which no efficacious therapies are available. We identified a pathway controlled by the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) that regulates astrocyte function during inflammation. Briefly, AhR in astrocytes promotes the expression of Suppressor Of Cytokine Signaling 2 (SOCS2), an inhibitor of NF-κB activation. AhR deletion in astrocytes up-regulates NF-κB activation and worsens EAE. These data suggest that AhR/SOCS2 signaling suppresses astrocyte pathogenic activities in EAE by limiting NF-κB activation. In support of this interpretation, nasal administration of the AhR agonist ITE suppresses EAE through a mechanism mediated by AhR in astrocytes. Moreover, agonists derived from dietary tryptophan (Trp) and the gut flora ameliorate EAE via AhR in astrocytes. These AhR agonists are decreased in MS patients, suggesting that deficient AhR activation contributes to disease pathogenesis. Collectively, these findings identify a novel AhR/SOCS2 pathway that integrates endogenous and environmental signals to control astrocyte function. We hypothesize that AhR in astrocytes limits CNS inflammation and is a potential therapeutic target for MS. Our specific aims are: SPECIFIC AIM 1: DOES AHR SUPPRESS ASTROCYTE-DRIVEN NEUROTOXICITY DURING EAE? We propose to: 1) Determine the effects of AhR in astrocytes on neurotoxicity during EAE, 2) Establish the effects of SOCS2 on NF-κB activation and astrocyte neurotoxicity, 3) Determine whether AhR limits NF-κB- driven astrocyte neurotoxicity via SOCS2. SPECIFIC AIM 2: HOW DOES AHR CONTROL THE TRANSCRIPTIONAL PROGRAM OF ASTROCYTES? We propose to: 1) Determine the role of AhR in the control of the transcriptional response of astrocytes during EAE, 2) Define the contribution of SOCS2 to the transcriptional effects of AhR in astrocytes, 3) Establish the heterogeneity of astrocyte responses and their control by AhR during EAE by single cell RNA-Seq. SPECIFIC AIM 3: IS AHR A THERAPEUTIC TARGET TO MODULATE ASTROCYTE FUNCTION? We propose to: 1) Evaluate the effects on astrocytes and CNS inflammation of AhR activation by ITE administered nasally, 2) Define the role of AhR/SOCS2 in astrocytes on the chronic progressive NOD EAE, which models important aspects of SPMS, 3) Evaluate the therapeutic value of nasal ITE in NOD EAE. IN SUMMARY, this project uses unique experimental systems to study the role of a novel AhR/SOCS2 pathway in astrocytes on CNS inflammation and its potential as a therapeutic target.