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TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn’s Disease Patients

Authors: Caër, Charles; Gorreja, Frida; Forsskåhl, Sophia K.; Brynjolfsson, Siggeir F.; Szeponik, Louis; Magnusson, Maria K.; Börjesson, Lars G.; Block, Mattias; Lindskog, Elinor Bexe; Wick, Mary Jo

Online: https://academic.oup.com/ecco-jcc/advance-article/doi/10.1093/ecco-jcc/jjab022/6127460

Issue: J Crohns Colitis . 2021 Feb 4;jjab022.


BACKGROUND AND AIMS: 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 IBD pathogenesis. 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. METHODS: 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 TNF antagonist antibodies. RESULTS: TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with the disease score. TREM-1 + cells, which are mainly immature macrophages and CD11b + granulocytes, increase among LP cells from Crohn’s patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn’s patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF. CONCLUSIONS: 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.