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

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

Title: TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients
Author: Caër, Charles
Gorreja, Frida
Forsskåhl, Sophia K.
Brynjólfsson, Siggeir Fannar
Szeponik, Louis
Magnusson, Maria K.
Börjesson, Lars G.
Block, Mattias
Bexe-Lindskog, Elinor
Wick, Mary Jo
Date: 2021-02-04
Language: English
Scope: 16
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Journal of Crohn's & colitis; 15(8)
ISSN: 1873-9946
DOI: https://doi.org/10.1093/ecco-jcc/jjab022
Subject: Bólgur; Crohns-sjúkdómur; Smáþarmar; Crohn’s disease; IL-6; intestinal inflammation; macrophages; TNF; TREM-1; Gene Expression; Humans; Macrophages/metabolism; Middle Aged; Crohn Disease/pathology; Granulocytes/metabolism; Male; CD11b Antigen/metabolism; Case-Control Studies; Young Adult; Triggering Receptor Expressed on Myeloid Cells-1/metabolism; Interleukin-6/metabolism; Intestinal Mucosa/metabolism; Aged, 80 and over; Adult; Female; Aged; Monocytes/metabolism; Gastroenterology
URI: https://hdl.handle.net/20.500.11815/2853

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Caër , C , Gorreja , F , Forsskåhl , S K , Brynjólfsson , S F , Szeponik , L , Magnusson , M K , Börjesson , L G , Block , M , Bexe-Lindskog , E & Wick , M J 2021 , ' TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients ' , Journal of Crohn's & colitis , vol. 15 , no. 8 , pp. 1346-1361 . https://doi.org/10.1093/ecco-jcc/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 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. 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 tumour necrosis factor [TNF] antagonist antibodies. RESULTS: 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. 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.


This work was funded by grants to M.J.W. from the Swedish Cancer Society [CAN2015/463 and CAN 2018/372] and to E.B.L. from the Swedish Government under the ALF agreement [ALFGBG-784211]. Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

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