Xu Zhu, Zhu Junyu, Ma Zhuo, Zhen Dan, Gao Zindan
Neurological Department, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
Guizhou Medical University, Guizhou, China.
Inflammation. 2024 Dec 16. doi: 10.1007/s10753-024-02195-z.
Multiple sclerosis (MS) and inflammatory bowel disease (IBD) are both autoimmune disorders caused by dysregulated immune responses. Still, there is a growing awareness of the comorbidity between MS and IBD. However, the shared pathophysiological mechanisms between these two diseases are still lacking. RNA sequencing datasets (GSE126124, GSE9686, GSE36807, GSE21942) were analyzed to identify the shared differential expressed genes (DEGs) for IBD and experimental allergic encephalomyelitis (EAE). Other datasets (GSE17048, GSE75214, and GSE16879) were downloaded for further verification and analysis. Shared pathways and regulatory networks were explored based on these DEGs. The single-cell transcriptome of central nervous system (CNS) immune cells sequenced from EAE brains and the public datasets of IBD (PRJCA003980) were analyzed for the immune characteristics of the shared DEGs. Mass cytometry by time-of-flight (CyTOF) of peripheral blood mononuclear cells (PBMCs) was performed for the systematic immune response in the EAE model. Machine learning algorithms were also used to identify the diagnostic biomarkers of MS. We identified 74 common DEGs from the selected RNA sequencing datasets, and single-cell RNA data of the intestinal tissues of IBD patients showed that 56 of 74 DEGs were highly enriched in IL1B macrophages. These 56 DEGs, defined as inflammation-related DEGs (IRGs), were also highly expressed in pro-inflammatory macrophages of EAE mice and MS patients. The abundance of systematic CD14 monocytes was validated by CyTOF data. These IRGs were highly enriched in immune response, NOD-like receptor signaling pathway, IL-18 signaling pathway, and other related pathways. In addition, 'AddModuleScore_UCell' analysis further validated that these IRGs (such as IL1B, S100A8, and other inflammatory factors) are highly expressed mainly in pro-inflammatory macrophages, which play an essential role in pro-inflammatory activation in IBD and multiple sclerosis, such as IL-17 signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway. Finally, suppressors of cytokine signaling 3(SOCS3) and formyl peptide receptor 2(FPR2) were identified as potential biomarkers by machine learning. Two genes were highly expressed in pro-inflammatory macrophages of IBD and MS disease compared to control, and other datasets and experiments further revealed that SOCS3 and FPR2 were highly expressed in IBD and EAE samples. These shared IRGs, which encode inflammatory cytokines, exhibit high expression levels in inflammatory macrophages in IBD and may play a significant role in the inflammatory cytokine storm in MS patients. Two potential biomarkers, SOCS3 and FPR2, were screened out with great diagnostic value for MS and IBD.
多发性硬化症（MS）和炎症性肠病（IBD）都是由免疫反应失调引起的自身免疫性疾病。尽管如此，人们对MS和IBD之间的共病现象的认识仍在不断提高。然而，这两种疾病之间共同的病理生理机制仍然缺乏。分析了RNA测序数据集（GSE126124、GSE9686、GSE36807、GSE21942），以确定IBD和实验性变应性脑脊髓炎（EAE）的共同差异表达基因（DEG）。下载了其他数据集（GSE17048、GSE75214和GSE16879）进行进一步验证和分析。基于这些DEG探索了共同的信号通路和调控网络。分析了从EAE脑测序的中枢神经系统（CNS）免疫细胞的单细胞转录组和IBD的公共数据集（PRJCA003980），以了解共同DEG的免疫特征。对EAE模型中外周血单个核细胞（PBMC）进行飞行时间质谱细胞术（CyTOF），以分析系统性免疫反应。还使用机器学习算法来识别MS的诊断生物标志物。我们从选定的RNA测序数据集中鉴定出74个共同的DEG，IBD患者肠道组织的单细胞RNA数据显示，74个DEG中的56个在IL1B巨噬细胞中高度富集。这56个DEG，被定义为炎症相关DEG（IRG），在EAE小鼠和MS患者的促炎巨噬细胞中也高度表达。通过CyTOF数据验证了系统性CD14单核细胞的丰度。这些IRG在免疫反应、NOD样受体信号通路、IL-18信号通路和其他相关通路中高度富集。此外，“AddModuleScore_UCell”分析进一步验证了这些IRG（如IL1B、S100A8和其他炎症因子）主要在促炎巨噬细胞中高表达，它们在IBD和多发性硬化症的促炎激活中起重要作用，如IL-17信号通路、NF-κB信号通路和TNF信号通路。最后，通过机器学习将细胞因子信号转导抑制因子3（SOCS3）和甲酰肽受体2（FPR2）鉴定为潜在的生物标志物。与对照组相比，这两个基因在IBD和MS疾病的促炎巨噬细胞中高表达，其他数据集和实验进一步表明SOCS3和FPR2在IBD和EAE样本中高表达。这些编码炎症细胞因子的共同IRG在IBD的炎症巨噬细胞中表现出高表达水平，可能在MS患者的炎症细胞因子风暴中起重要作用。筛选出了两个对MS和IBD具有重要诊断价值的潜在生物标志物SOCS3和FPR2。
