Abstract Background Despite advances in biologic therapies for Crohn’s disease (CD), many patients remain unresponsive, resulting in an efficacy ceiling in treatment options. Current treatments primarily target the adaptive immune system, without addressing innate immune-driven inflammation. This has created a significant unmet need in patient care1. Triggering receptor expressed on myeloid cells–1 (TREM-1), a key amplifier of the innate immune response, has emerged as a promising target due to its role in sustaining inflammation leading to disrupted mucosal integrity, and tissue damage in inflammatory bowel disease. Characterising TREM1 expression and activity in CD tissue strengthens its link to disease pathobiology and highlights its potential as a therapeutic target2,3. Methods To evaluate the association between TREM-1 and Crohn’s pathology, in situ assays and H-score calculations were used to quantify TREM1 mRNA and TREM-1 protein in lesional and non-lesional Crohn’s patient tissue resections. Spatial proteomics were performed to further refine TREM1 protein expression in specific cell types associated with inflammatory lesions. TREM-1 pathway activation was inferred from a proximity ligation assay designed to detect the interaction between the TREM-1 receptor and its obligate signalling adaptor, DAP12. Results TREM-1 expression was localised in areas of activated myeloid cells within inflammatory regions of luminal CD patient tissue, suggesting increased TREM-1 activity in progressive mucosal inflammation. Ulcer pathology within inflammatory areas in lesional tissue showed significantly elevated TREM1 mRNA and TREM-1 protein expression, as indicated by higher H-scores, compared to uninflamed mucosa (Fig. 1A). Spatial proteomics localised increased TREM-1 protein immunoreactivity to myeloid cells, including neutrophils, monocytes, and activated macrophages. Proximity ligation assay confirmed the potential for increased TREM-1 pathway activity in Crohn’s pathology. While TREM-1 and DAP12 protein expression was detected in tonsil, uninflamed and inflamed Crohn’s small intestine, increased interaction between these proteins was only found in inflamed mucosa and ulcer pathology (Fig. 1B). Conclusion TREM-1 expression is increased in activated myeloid cells within pathogenic lesions in Crohn’s resections, including areas of acute inflammation and ulceration. TREM-1 and DAP12 interaction was also observed in these same areas of pathology, suggesting TREM-1 pathway activation associated with disease pathology. These findings highlight the potential of TREM-1 as a promising therapeutic target in the treatment of CD due to its expression and activity in diseased tissue. References: 1 Vinolo E, Maillefer M, Jolly L, Colné N, Meiffren G, Carrasco K, et al. The potential of targeting TREM-1 in IBD. Adv Pharmacol. 2024;101:301-330. doi:10.1016/bs.apha.2024.10.010 2 Brynjolfsson SF, Magnusson MK, Kong PL, Jensen T, Kuijper JL, Håkansson K, et al. An Antibody Against Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Dampens Proinflammatory Cytokine Secretion by Lamina Propria Cells from Patients with IBD. Inflamm Bowel Dis. 2016;22(8):1803-1811. doi:10.1097/mib.0000000000000822 3 Schenk M, Bouchon A, Seibold F, Mueller C. TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest. 2007;117(10):3097-3106. doi:10.1172/jci30602 Conflict of interest: Patel, Priyank: Employee- Boehringer Ingelheim Bleck, Marina: Employee- Boehringer Ingelheim Pharmaceuticals, Inc. Invited speaker- Global Engage, Oxford Global McNabola, Angela: Employee- Boehringer Ingelheim Perez, Rocio: Employee- Boehringer Ingelheim Dr. Schmitz, Jochen: Employee- Boehringer Ingelheim Stock Ownership- Rigel Pharmaceutical, Dynavax, Merck, Eli Lilly and Company The study was supported and funded by Boehringer Ingelheim. Klimowicz, Alexander: Employee- Boehringer Ingelheim
Patel et al. (Thu,) studied this question.