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

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

  • Atherosclerosis. 2026 Apr:415:120701. doi: 10.1016/j.atherosclerosis.2026.120701.
Mengting Jiang 1,  Yingqian Zhang 2,  Xiaohang Yuan 2,  Yuxing Chen 2,  Yan Han 2,  Xietian Pan 2,  Xi Zhang 2,  Haoyi Ye 2,  Wei Wang 2,  Wei Tong 3,  Lei Gao 4
Affiliations

Affiliations

  • 1 Senior Department of Cardiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Department of Cardiology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
  • 2 Senior Department of Cardiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
  • 3 Senior Department of Cardiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: [email protected].
  • 4 Senior Department of Cardiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: [email protected].
PMID: 41832836 DOI: 10.1016/j.atherosclerosis.2026.120701
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 = 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 ± 0.41 vs. 2.10 ± 0.68 mm2, P = 0.045]; 48.7% at 3 months [2.18 ± 0.49 vs. 4.25 ± 1.33 mm2, P = 0.005]) and neointimal thickness at 3 months (383.02 ± 59.54 vs. 555.63 ± 136.26 μm, P = 0.004) without impairing stent endothelialization. LR12 promoted a shift in macrophage polarization towards anti-inflammatory M2 type (decreased TNF-α/ARG-1 ratio, P < 0.05) and suppressed systematical and local pro-inflammatory cytokines (IL-6, IL-12; P < 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.

Keywords

In-stent neoatherosclerosis; JAK1-STAT1/STAT3 pathway; Macrophage polarization; Triggering receptor expressed on myeloid cells-1.

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