P0102TREM-1 as a contributing driver of inflammatory pathways in Crohńs disease

Background Biologic therapies for Crohn’s disease (CD) often fail to address innate immune-driven inflammation, leaving many patients unresponsive and inadequately managed1. Triggering receptor expressed on myeloid cells-1 (TREM-1) has been identified as a potential therapeutic target in inflammatory bowel disease (IBD)1. Microbial stimuli upregulate TREM-1 in intestinal myeloid cells, amplifying innate immune responses via the additional cross-interaction of increased Toll-like receptor (TLR) and Nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) signalling2,3. Peptidoglycan recognition protein 1 (PGLYRP1), an endogenous neutrophil derived ligand, forms complexes with bacterial derived peptidoglycans and binds TREM-1. TREM-1 promotes pro-inflammatory mediators that disrupt epithelial integrity1,2,4 and sustain inflammation in CD1,3. TREM-1 inhibition may therefore interfere with these pathologic processes. Understanding its biology is key to evaluating its therapeutic role in IBD1. Methods Primary human monocytes were stimulated with different concentrations of peptidoglycans (PGN-BS) in the presence of PGLYRP1 to assess the type and extent of their response. Proteomic and transcriptomic profiling, including MSD analysis, Olink profiling, TaqMan, and RNA-seq, was used to identify a monocyte-specific signature and to correlate the unique profile (protein, gene expression) with function. These results were then mapped onto patient datasets using monocyte RNA-seq signatures to link to disease pathology. Results Stimulation of primary cells with PGN/PGLYRP1 led to a dose-dependent release of pro-inflammatory cytokines and enhanced TREM-1 signalling, particularly in monocytes. This increase in TREM-1 expression was also observed in areas of acute inflammation and ulceration. Transcriptomic and proteomic analyses revealed a consistent upregulation of pro-inflammatory mediators, which were used to construct a TREM-1 activation gene module. This module was subsequently transposed onto disease expression datasets from CD patients, revealing a persistent elevation of the TREM-1 gene signature in both myeloid and non-myeloid cells within inflamed ileal tissue. Conclusion TREM-1 signature elevation in myeloid and non-myeloid cells in inflamed ileal tissue, particularly in ulcerated regions, underscores its relevance in CD. PGN/PGLYRP1-induced dose-dependent cytokine release and enhanced TREM-1 signalling in monocytes support its role in driving acute inflammation. Transcriptomic and proteomic signatures resembling CD patient biopsies further support targeting TREM-1 to address unmet clinical needs in CD. 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] Arts RJW, Joosten LAB, Meer JWM, Netea MG. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukocyte Biol. 2013;93(2):209-215. doi:10.1189/jlb.0312145 [3] 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 [4] Read CB, Kuijper JL, Hjorth SA, Heipel MD, Tang X, Fleetwood AJ, et al. Cutting Edge: Identification of Neutrophil PGLYRP1 as a Ligand for TREM-1. J Immunol. 2015;194(4):1417-1421. doi:10.4049/jimmunol.1402303 Conflict of interest: Perez, Rocio: Employee- Boehringer Ingelheim Sheehan, Ryan: Employee- Boehringer Ingelheim Webb, Deborah: 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.