共生菌群在NLRP3+/R258W突变小鼠皮肤自发炎症中的作用研究

Skin is the largest organ of human body, is a physical barrier that prevents pathogenic entrance. There is a delicate balance between the host and the commensal microbiota on the skin surface, which is critical to maitain immune homeostasis and health. However, our understanding about the interaction between host and commensal microbiota is still lacking. The NLRP3+/R258W mouse line is an important model for studying skin inflammation and immunity. Our preliminary data showed that the severity of skin inflammation of NLRP3+/R258W mice was different in novel feeding conditions. Our analysis of the microbiota data also revealed candidate bacterial strains likely contributing to the skin inflammation. In the current project, we will use NLRP3+/R258W mutant mice on either C57BL/6 or BALB/C genetic background to throughly analyze gut-microbiot and skin-microbiota, isolate key bacteria strains and conduct functional studies, aiming to explore the mechanism of microbiota contribution to skin inflammation.

皮肤是人体最大的器官，是阻止外来病原体进入人体的物理屏障。皮肤表面宿主和共生菌群之间动态的相互调控是维持免疫平衡的重要环节，但目前对菌群-宿主相互作用的理解仍然有限。NLRP3+/R258W功能获得性突变小鼠是研究皮肤炎症和免疫的重要模型。我们的初步研究显示不同的饲养环境使得该突变小鼠的肠道菌群发生变化从而导致皮肤炎症差异，而且初步分析确认了导致这些差异的关键菌种。本研究将在此基础上利用C57BL/6和BALB/C遗传背景的NLRP3+/R258W功能获得性突变小鼠，通过菌群分析、菌株分离、功能重构等一系列实验，探索共生菌群影响皮肤炎症的机理。

本项目的研究包括基础和应用两个部分。在基础研究方面，我们发现决定NLRP3+/R258W突变小鼠皮肤自发炎症的主要肠道菌贡献，如果3.5周龄后定植Coribacteriales属的ASV-48或ASV-87，NLRP3+/R258W小鼠择趋向后续有炎症产生。 进而促使盲肠、回肠及结肠的Toll样受体4(TLR4)显著升高，进而使盲肠、回肠及结肠表达CCL28、NLRP3、TNF-α和IL-β含量升高，产生更多的IgA使血液中的IgA含量升高，以及皮肤的炎症因子IL-β和IL-6显著升高皮肤炎症增强。应用方面因为针对新冠疫情的紧急研发，我们从细菌中研发了针对抗新冠病毒和流感病毒的候选药物CPAVM1，已经申请了专利1项。以上发现为细菌与宿主及生态的关系提供了新的思路。在本项目的资助下，已经发表研究论文及论著 2 篇，申请专利 1 项。