Tang Mi, Xiong Liling, Cai Jianghui, Gong Xuejia, Fan Li, Zhou Xiaoyu, Xing Shasha, Yang Xiao
Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, People's Republic of China.
School of medicine, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
J Inflamm Res. 2024 Sep 30;17:6863-6874. doi: 10.2147/JIR.S471374. eCollection 2024.
Intrahepatic cholestasis of pregnancy (ICP) is a disorder that characterized by maternal pruritus, abnormal liver function, and an elevation in total bile acid concentrations during pregnancy. Immune factors have been recognized as playing a vital role in the mechanism of ICP. However, the underlying mechanisms regulating dysfunctional immune cells and immune genes remain to be fully elucidated.
Single-cell RNA sequencing and bulk RNA sequencing data of the placenta were downloaded from the SRA database. The AUCell package, Monocle package and SCENIC package were utilized to explored immune cell activity, cell trajectory and transcription factor, respectively. GO, KEGG, and GSEA were employed to explore potential biological mechanisms. Cell-cell communications were further investigated using the CellChat package. RT-PCR, and Western blot were used to verify the gene expression in placenta.
In placenta cells, macrophages were found to be significantly increased in ICP. Additionally, macrophages exhibited the highest immune gene score and were divided into four subclusters (MF1-4). Our analysis revealed significant elevations in MF2, associated with LPS response and antigen presentation, and MF4, associated with TNF and cytokine production. MF3 displayed an anti-inflammatory phenotype. MF1, closely related to ribosomes and proteins, exhibited a sharp decrease. Although ICP maintained an anti-inflammatory state, macrophage trajectories showed a gradual progression toward inflammation. Subsequently, we confirmed that cytokine- and chemokine-related signaling pathways were emphasized in macrophages. Within the CXCL signaling pathway, the increased expression of CXCL1 in macrophages can interact with CXCR2 in neutrophils, potentially inducing macrophage infiltration, stimulating neutrophil chemotaxis, and leading to an inflammatory response and cellular damage.
In conclusion, we firstly revealed the transcriptional signatures of macrophages in ICP and discovered a tendency toward an inflammatory state. This study also provides new evidence that the CXCL1-CXCR2 axis may play an important role in the pathogenesis of ICP.
妊娠期肝内胆汁淤积症（ICP）是一种在孕期以母体瘙痒、肝功能异常以及总胆汁酸浓度升高为特征的病症。免疫因素在ICP的发病机制中被认为起着至关重要的作用。然而，调节功能失调的免疫细胞和免疫基因的潜在机制仍有待充分阐明。
从SRA数据库下载胎盘的单细胞RNA测序和批量RNA测序数据。分别利用AUCell软件包、Monocle软件包和SCENIC软件包来探究免疫细胞活性、细胞轨迹及转录因子。采用GO、KEGG和GSEA来探究潜在的生物学机制。使用CellChat软件包进一步研究细胞间通讯。采用RT-PCR和蛋白质免疫印迹法验证胎盘中的基因表达。
在胎盘细胞中，发现ICP患者的巨噬细胞显著增多。此外，巨噬细胞表现出最高的免疫基因评分，并被分为四个亚群（MF1 - 4）。我们的分析显示，与LPS反应和抗原呈递相关的MF2以及与TNF和细胞因子产生相关的MF4显著升高。MF3表现出抗炎表型。与核糖体和蛋白质密切相关的MF1则显著减少。尽管ICP维持着抗炎状态，但巨噬细胞轨迹显示出逐渐向炎症发展的趋势。随后，我们证实巨噬细胞中细胞因子和趋化因子相关信号通路被增强。在CXCL信号通路中，巨噬细胞中CXCL1表达的增加可与中性粒细胞中的CXCR2相互作用，可能诱导巨噬细胞浸润，刺激中性粒细胞趋化，并导致炎症反应和细胞损伤。
总之，我们首次揭示了ICP中巨噬细胞的转录特征，并发现了向炎症状态发展的趋势。本研究还提供了新的证据，表明CXCL1 - CXCR2轴可能在ICP的发病机制中起重要作用。
