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

CD83对维持肠道代谢和免疫稳态的影响

• 批准号: 460744534
• 负责人: Professor Dr. Jochen Mattner
• 金额: --
• 依托单位: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/460744534?language=en
• 关键词: Impact; CD83; maintenance; intestinal; metabolic

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.

肠道菌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，微生物群的破坏以及随后免疫和代谢活性分子可用性的改变通常与感染介导的结肠炎或炎症性肠病（IBD）有关。然而，到目前为止，微生物群参与的途径以及它们与宿主的相互作用尚未完全揭示。CD83是免疫球蛋白受体超家族的一员，在髓细胞或上皮细胞上表达时局部影响免疫应答和微生物存活，以可溶性形式释放时远距离影响免疫应答和微生物存活。有趣的是，只有特定的细菌会引起dc释放可溶性CD83 （sCD83）。为了了解CD83的细胞特异性生物学，我们产生了条件CD83-/- (cCD83-/-)小鼠。在急性沙门氏菌感染dc特异性cCD83-/-动物时，细菌复制和易位减少与诱导轻度结肠炎相关，而慢性感染促进dc的炎症和糖酵解改变。因此，这些数据强烈表明，dc特异性CD83缺失会使急性细菌感染的清除永久化，但会损害慢性炎症的消退。相比之下，肠上皮细胞特异性cCD83-/-小鼠则屈服于胃肠道病原体的感染。因此，我们假设CD83以细胞特异性的方式调节肠道炎症、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CD83表达的影响，（ii）定义对细菌清除和炎症解决至关重要的CD83表达细胞亚群，（iii）确定CD83对肠道微生物群组成和分布的影响。（iv）表征影响小鼠CD83表达和释放及下游信号通路的微环境和代谢产物；(v)通过分析患者样本中CD83的表达和释放，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CD83分子的表征和CD83在微生物驱动的粘膜炎症过程中活化的分子机制的分析，不仅有助于提高对IBD和感染性结肠炎发病机制的理解，而且可能还允许开发新的治疗策略，这些治疗方法是治疗这些广泛和破坏性疾病所迫切需要的。