Impact of CD83 on the maintenance of intestinal metabolic and immune homeostasis

肠道微生物群介导对肠道病原体的定植抗性，并影响抗炎介质的可用性。因此，破坏的微生物群和随后改变的免疫和代谢活性分子的可用性通常与感染介导的结肠炎或炎症性肠病（IBD）相关。然而，到目前为止，微生物群参与的途径及其与宿主的相互作用尚未完全揭示。CD 83是免疫球蛋白受体超家族的成员，当在骨髓或上皮细胞上表达时局部影响免疫应答和微生物存活，并且当以其可溶形式释放时通过长距离影响免疫应答和微生物存活。有趣的是，只有某些细菌引起DC释放可溶性CD 83（sCD 83）。为了理解CD 83的细胞特异性生物学，我们产生了条件性CD 83-/-（cCD 83-/-）小鼠。虽然在DC特异性cCD 83-/-动物的急性沙门氏菌感染期间，细菌复制和易位减少与轻度结肠炎的诱导相关，但慢性感染促进了DC中的炎症和糖酵解改变。因此，这些数据强烈表明DC特异性CD 83缺失使急性细菌感染的清除永久化，但损害慢性炎症的消退。相反，肠上皮细胞特异性cCD 83-/-小鼠死于胃肠道病原体感染。因此，我们假设CD 83以细胞特异性方式调节肠道炎症、代谢和微生物存活。为了揭示这些表型背后的致病机制，我们的目标是（i）探索微生物和炎症对CD 83表达的影响，（ii）定义对细菌清除和炎症消退至关重要的表达CD 83的细胞亚群，（iii）确定CD 83对肠道微生物群的组成和分布的影响，（iv）表征影响小鼠中CD 83和下游信号传导途径的表达和释放的微环境和代谢产物;以及（v）通过分析患者样本的CD 83表达和释放，将我们在临床前模型中获得的发现转化为人类疾病。免疫调节CD 83分子的表征和微生物驱动的粘膜炎症过程中CD 83活化后的分子机制分析不仅有助于更好地理解IBD和感染性结肠炎的发病机制，而且还可能允许开发治疗这些广泛和毁灭性疾病迫切需要的新的治疗策略。

The gut microbiota mediates colonization resistance against intestinal pathogens and affects the availability of anti-inflammatory mediators. Thus, disrupted microbiota and subsequent altered availability of immune and metabolic active molecules are frequently associated with infection-mediated colitis or inflammatory bowel disease (IBD). The pathways engaged by the microbiota, however, and their mutual interaction(s) with the host have not been completely uncovered so far. CD83, a member of the immunoglobulin receptor super-family, affects immune responses and microbial survival locally when expressed on myeloid or epithelial cells and via long distances when released in its soluble form. Interestingly, only certain bacteria elicit the release of soluble CD83 (sCD83) by DCs . To understand the cell-specific biology of CD83, we generated conditional CD83-/- (cCD83-/-) mice. While a reduced bacterial replication and translocation correlated with the induction of a mild colitis during acute Salmonella infection of DC-specific cCD83-/- animals, chronic infection promoted inflammation and altered glycolysis in DCs. Thus, these data strongly suggest that a DC-specific CD83 deletion perpetuates the clearance of acute bacterial infections, but impairs the resolution of chronic inflammation. Intestinal epithelial cell-specific cCD83-/- mice, in contrast, succumbed to infections with gastrointestinal pathogens. Thus, we hypothesize that CD83 modulates intestinal inflammation, metabolism and microbial survival in a cell-specific manner. To uncover the pathogenic mechanisms underlying these phenotypes, we aim to (i) explore the impact of microbes and inflammation on CD83 expression, (ii) define the CD83-expressing cell subsets crucial for bacterial clearance and the resolution of inflammation, (iii) determine the effect(s) of CD83 on the composition and distribution of intestinal microbiota, (iv) characterize the microenvironmental and metabolic products affecting expression and release of CD83 and downstream signaling pathways in mice; and (v) translate our findings obtained in preclinical models into human disease by analysing patient samples for CD83 expression and release. The characterization of the immunemodulating CD83 molecule and the analysis of the molecular mechanisms following CD83 activation during microbe-driven mucosal inflammation might not only contribute to an improved understanding of the pathogenesis of IBD and infectious colitis, but might also allow the development of novel therapeutic strategies that are urgently needed for the treatment of these widespread and devastating diseases.