BACKGROUND Myeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269-78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957-70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524-34, 2017). RESULTS We performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation. CONCLUSIONS We conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

中文翻译：

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IBD 患者发炎的结肠中富含单核吞噬细胞亚群。


背景技术骨髓细胞，特别是单核吞噬细胞，包括单核细胞、巨噬细胞和树突细胞(DC)，在先天免疫以及适应性免疫的启动和维持中发挥重要作用。虽然已经在炎症性肠病(IBD)患者中鉴定和评估了T细胞相关的激活途径和细胞因子(Neurath, Nat Rev Gastroenterol Hepatol 14:269-78, 1989)，但单核吞噬细胞的作用却知之甚少。最近的报告支持 DC 亚群在急性结肠炎模型发展中的关键作用 (Arimura et al., Mucosal Immunol 10:957-70, 2017)，并表明它们可能通过诱导 Th1 促进溃疡性结肠炎 (UC) 的发病机制/Th2/Th17 反应（Matsuno 等人，Inflamm Bowel Dis 23:1524-34, 2017）。结果我们进行了计算机分析并评估了免疫细胞的富集，重点是 IBD 患者结肠活检中的单核吞噬细胞。样本来自不同的肠道位置，具有不同的疾病严重程度以及对当前疗法的治疗反应。我们观察到来自不同肠道位置的发炎组织中单核细胞、M1 巨噬细胞、活化 DC (aDC) 和浆细胞样树突细胞 (pDC) 的富集。这种富集与疾病的严重程度相关。此外，相同的单核吞噬细胞亚群是英夫利昔单抗和维多珠单抗治疗无反应样本中最富集的细胞类型之一。我们根据源自 DC 和单核细胞的单细胞 RNA-seq (scRNA-seq) 研究的基因特征，进一步研究了选定 DC 和单核细胞亚群的富集情况（Villani 等人，Science 356：eaah4573，2017），并且已验证发炎组织和具有治疗抗性的组织中的富集。 此外，我们在代表慢性炎症的 C57Bl/6 小鼠中验证了葡聚糖硫酸钠 (DSS) 诱导的结肠炎模型中单核吞噬细胞亚群丰度的增加。结论 我们对 IBD 患者结肠样本中的免疫细胞群进行了广泛分析，并鉴定了发炎组织中丰富的单核细胞、巨噬细胞和树突状细胞亚群。了解它们如何与结肠微环境中的其他免疫细胞和其他细胞（如上皮细胞和基质细胞）相互作用，将有助于我们描述疾病的发病机制。