Impact of intestinal myeloid cells on the immune-neuronal crosstalk in the pathogenesis of synucleinopathies and colitis

炎症性肠病（IBD）和慢性神经退行性疾病在流行病学上是相关的，并且出乎意料地共享与炎症过程相关的基因位点。以α-突触核蛋白（α-Syn）在脑内聚集为特征的神经退行性疾病，因此被称为突触核蛋白病，表现出复杂神经功能的进行性下降，但也经常与肠道功能障碍相关，这种功能障碍通常在病程早期和先前的典型运动症状中表现出来。相反，可能由白质病变和自主神经病变引起的神经系统症状（如嗅觉功能下降、认知能力下降、焦虑和抑郁增加）经常在炎症性肠病（IBD）患者中观察到，这些患者患有慢性肠道炎症，其病因仅部分了解。这些临床数据总体上表明，这两种疾病可能有共同的，迄今尚未发现的病理机制根源。在初步研究中，我们提供了强有力的实验证据，证明在结肠炎期间，大脑中存在显著的髓系细胞来源的特征，而反过来，神经退行性疾病状态导致肠道组织显著的促炎印记。总的来说，到目前为止，我们的数据为我们的假设提供了强有力的支持，即髓系细胞来源的细胞群-包括脑内小胶质细胞，巨噬细胞，炎症单核细胞和树突状细胞-可能在突触病变和IBD之间的病理机制联系中发挥重要作用。因此，在我们的项目中，我们试图破译骨髓细胞驱动的免疫信号从肠道到cns驻留细胞的细胞和分子影响，反之亦然，在突触核蛋白病和IBD的背景下。我们的长期目标是解开骨髓细胞依赖过程，以确定和理想的功能测试新的治疗靶点，以预防或至少限制IBD和突触核蛋白病的疾病进展炎症途径。

Inflammatory bowel disease (IBD) and chronic neurodegenerative diseases are epidemiologically linked, and unexpectedly share gene loci related to inflammatory processes. Neurodegenerative diseases, characterized by α-Synuclein (α-Syn) aggregation in the brain, and therefore termed synucleinopathies, display a progressive decline of complex neurologic abilities but are also frequently associated with intestinal dysfunction that manifests often early in the diseases course and prior typical motoric symptoms. Conversely, neurologic symptoms (e.g. reduction of olfactory function, cognitive decline, increased anxiety, and depression) potentially caused by white matter lesions and autonomic neuropathy are often observed in inflammatory bowel disease (IBD) patients suffering from chronic intestinal inflammation of only partially understood etiology. These clinical data overall suggest that both diseases may have common, so far undiscovered pathomechanistic roots. In preliminary studies, we provide strong experimental evidence for the presence of a significant myeloid cell-derived signature in the brain during colitis while reciprocally, neurodegenerative disease states lead to a notably pro-inflammatory imprinting of intestinal tissues. Overall, our data so far provide compelling support for our hypothesis that myeloid lineage-derived cell populations – including brain-resident microglia, macrophages, inflammatory monocytes, and dendritic cells – may play an important role providing a pathomechanistic link between syncleinopathies and IBD. Hence, in our project, we seek to decipher the cellular and molecular impact of myeloid cell-driven immune signals from the gut to CNS-resident cells and vice versa in the context of synucleinopathies and IBD. Our long-term goal is to disentangle myeloid cell-dependent processes in order to identify and ideally functionally test novel therapeutic targets to prevent or at least limit disease-progressing inflammatory pathways in IBD and synucleinopathies.