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

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.