Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
J Crohns Colitis. 2021 Aug 2;15(8):1346-1361. doi: 10.1093/ecco-jcc/jjab022.
Uncontrolled activation of intestinal mononuclear phagocytes [MNPs] drives chronic inflammation in inflammatory bowel disease [IBD]. Triggering receptor expressed on myeloid cells 1 [TREM-1] has been implicated in the pathogenesis of IBD. However, the role of TREM-1+ cell subsets in driving IBD pathology and the link with clinical parameters are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy.
TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria [LP] layers, and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media [LP-CM] from patients in the presence or absence of TREM-1 and tumour necrosis factor [TNF] antagonist antibodies.
TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with disease score. TREM-1+ cells, which are mainly immature macrophages and CD11b+ granulocytes, increase among LP cells from Crohn's disease patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn's disease patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF.
High intestinal TREM-1 expression, reflecting a high frequency of TREM-1+ immature macrophages and TREM-1+CD11b+ granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.
肠道单核吞噬细胞[MNP]的失控激活驱动炎症性肠病[IBD]的慢性炎症。髓样细胞表达的触发受体 1[TREM-1]已被牵涉到 IBD 的发病机制中。然而，TREM-1+细胞亚群在驱动 IBD 病理中的作用及其与临床参数的联系尚不清楚。我们研究了 TREM-1 在人类肠道 MNP 亚群中的表达，并研究了阻断 TREM-1 作为潜在的 IBD 治疗方法。
分析了对照和 IBD 患者的肠道黏膜、富含上皮和固有层[LP]层以及纯化细胞中 TREM-1 的基因表达。通过流式细胞术和免疫荧光显微镜评估免疫细胞上的 TREM-1 蛋白。使用 TREM-1 激动剂或来自患者的 LP 条件培养基[LP-CM]，在存在或不存在 TREM-1 和肿瘤坏死因子[TNF]拮抗剂抗体的情况下，通过大规模基因表达检测血液单核细胞的激活。
IBD 患者的肠道黏膜中 TREM-1 基因表达增加，并与疾病评分相关。TREM-1+细胞主要是未成熟的巨噬细胞和 CD11b+粒细胞，在克罗恩病患者的 LP 细胞中增加，其频率与 LP-CM 中的炎症分子相关。来自克罗恩病患者的 LP-CM 在血液单核细胞中诱导炎症转录组，包括增加的 IL-6 表达，同时阻断 TREM-1 和 TNF 可降低其表达。
高肠道 TREM-1 表达反映了 TREM-1+未成熟巨噬细胞和 TREM-1+CD11b+粒细胞的高频率，与 IBD 患者的有害炎症微环境相关。因此，阻断 TREM-1 途径，特别是同时与抗 TNF 治疗联合，具有作为新的 IBD 治疗方法的潜力。
