TREM-1 inhibition with LR12 attenuates in-stent neoatherosclerosis through modulating macrophage polarization in a rabbit model: An optical coherence tomography study.

Abstract

BACKGROUND: In-stent neoatherosclerosis (ISNA) contributes significantly to late stent thrombosis and in-stent restenosis. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a key amplifier of inflammation; however, its role in ISNA pathogenesis remains unexplored. In this study, we investigated the effects of pharmacologically inhibiting TREM-1 with a novel clinical agent LR12 (nangibotide) on ISNA development in an experimental model. METHODS: A rabbit model of ISNA was established using high-fat diet (HFD)-fed male New Zealand rabbits (3-4 months old) undergoing aortic balloon angioplasty and implantation of a second-generation drug-eluting stent. A total of 40 rabbits were randomized to receive the TREM-1 inhibitor LR12 or saline post-stenting, with endpoints assessed at 1 and 3 months (n&#xa0;=&#xa0;10). Optical coherence tomography (OCT) evaluated ISNA formation and stent healing. Serum biomarkers, histopathology, immunofluorescence, and in vitro macrophage polarization studies were performed. RESULTS: OCT demonstrated LR12 markedly attenuated ISNA area (40.5% reduction at 1 month [1.25&#xa0;&#xb1;&#xa0;0.41 vs. 2.10&#xa0;&#xb1;&#xa0;0.68&#xa0;mm, P&#xa0;=&#xa0;0.045]; 48.7% at 3 months [2.18&#xa0;&#xb1;&#xa0;0.49 vs. 4.25&#xa0;&#xb1;&#xa0;1.33&#xa0;mm, P&#xa0;=&#xa0;0.005]) and neointimal thickness at 3 months (383.02&#xa0;&#xb1;&#xa0;59.54 vs. 555.63&#xa0;&#xb1;&#xa0;136.26&#xa0;&#x3bc;m, P&#xa0;=&#xa0;0.004) without impairing stent endothelialization. LR12 promoted a shift in macrophage polarization towards anti-inflammatory M2 type (decreased TNF-&#x3b1;/ARG-1 ratio, P&#xa0;<&#xa0;0.05) and suppressed systematical and local pro-inflammatory cytokines (IL-6, IL-12; P&#xa0;<&#xa0;0.05). Mechanistically, TREM-1 inhibition reduced ox-LDL-induced foam cell formation and modulated macrophage polarization via the JAK1-STAT1/STAT3 pathway in vitro. CONCLUSIONS: Pharmacological inhibition of TREM-1 using LR12 effectively suppresses ISNA development without compromising stent healing, probably by inhibiting pro-inflammatory M1 polarization and promoting anti-inflammatory M2 macrophage phenotypes through modulation of the JAK1-STAT1/STAT3 signaling pathway. These results motivate further trials evaluating LR12 as a promising therapeutic strategy targeting inflammation to prevent ISNA in patients.