Skip to content
DraconiticResearch
Search Sources API
201,818 studies31 sourcesUpdated 26 min ago
Peer-reviewedCC BY-NC-NDInternational Immunopharmacology

CXCL16 promotes macrophage-driven inflammation and vascular smooth muscle cell phenotypic switching during carotid plaque destabilization

  • Guoqing Yao1
  • Tiankuo Luan2
  • Daqiang Song3
  • Guojing Liu4
  • Xuemei Hu5
  • Yangyang Feng1
  • Rui Liang6
  • Yu Zhao7
  • H LIU8
8 affiliations
  1. 1Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
  2. 2Department of Anatomy, Chongqing Medical University, Chongqing 400016, China
  3. 3Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
  4. 4Department of Neurosurgery, The University-Town Hospital of Chongqing Medical University, Chongqing 400016, China
  5. 5Department of Endocrinology, The People's Hospital of Rongchang District, Chongqing 402460, China
  6. 6Institute for Laboratory Animals Research, Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China
  7. 7Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected]
  8. 8Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Day Service Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected]
Open at sourceDOICite

Abstract

Carotid plaque instability is a major determinant of ischemic stroke and is characterized by heightened inflammation and structural remodeling of the vessel wall. Although macrophages and vascular smooth muscle cells (VSMCs) are central to plaque vulnerability, the mechanisms coordinating immune activation with vascular remodeling remain incompletely understood. Bulk transcriptomic data from multiple Gene Expression Omnibus (GEO) datasets were integrated to compare unstable and stable carotid plaques. Differential gene expression analysis, weighted gene co-expression network analysis, immune-gene curation, and machine learning methods (least absolute shrinkage and selection operator [LASSO] and random forest) were used to identify key genes and construct a nomogram. The findings were validated using independent datasets, single-cell RNA sequencing, and human carotid plaque specimens. The mechanistic roles of CXCL16 were examined using macrophage functional assays, NF-κB inhibition, VSMC co-culture with macrophage-conditioned media, and the establishment of an ApoE −/− carotid atherosclerosis model with local CXCL16 suppression. Cell-cell communication and pseudotime analyses were performed to explore macrophage-VSMC interactions. CXCL16 , CCL2 , and MMP9 were consistently upregulated in unstable plaques and showed robust diagnostic performance across datasets. A three-gene nomogram generated from this study suggested potential clinical utility. Single-cell analyses indicated that CXCL16 was enriched in plaque-associated M1 macrophages and was associated with inflammatory activation states. Human plaque staining confirmed higher CXCL16/CCL2/MMP9 expression in unstable plaques with increased macrophage and leukocyte infiltration. In vitro, CXCL16 knockdown attenuated NF-κB activation and reduced downstream inflammatory mediators (including CCL2), accompanied by decreased macrophage migration; NF-κB inhibition phenocopied these effects. In vivo, CXCL16 suppression reduced carotid plaque formation and inflammatory cell infiltration. Cell-cell communication analysis revealed enhanced SPP1/osteopontin signaling from M1 macrophages toward VSMCs, with higher SPP1 expression in CXCL16-high M1 macrophages. Co-culture experiments showed that macrophage-derived CXCL16 promoted VSMC migration and phenotypic switching, which was reversed by CXCL16 knockdown. CXCL16 acts as a central inflammatory mediator in carotid plaque destabilization by promoting NF-κB–dependent macrophage activation and migration. It also enhances SPP1/osteopontin-associated macrophage-VSMC crosstalk that drives phenotypic remodeling in VSMCs. Our results collectively suggest CXCL16 as a diagnostic biomarker and a potential therapeutic target for carotid atherosclerosis. • CXCL16 drives carotid plaque destabilization by promoting macrophage inflammation and VSMC switching. • Transcriptomic and single-cell analyses highlight CXCL16 as a key inflammatory mediator in plaque instability. • CXCL16 suppression reduces macrophage activation and VSMC migration, suggesting a therapeutic target.

Related

  1. Acute respiratory distress syndrome FXR/Sptlc2 signaling promotes alveolar macrophage mitophagy and limits lung inflammation
    Mi Yan, Yanfei Liu, Mengsheng Deng +13
    Cell ReportsPeer-reviewedCC BY 4.0Full textGeneral biologyCrossrefDOAJ
  2. An opsonic peptide promotes radiation-induced macrophage extracellular trap clearance to alleviate inflammation
    Yongchan Lee, Gaifeng Ma, Dilara Aylar +2
    Frontiers in ImmunologyPeer-reviewedCC BY 4.0Full textImmunologyCrossrefEurope PMC
  3. Oncogenic CLDN1 promotes thyroid cancer progression through TAp63-mediated glycolytic switching
    Bowei Zhang, Jinju Wang, Qianxi Zhang +1
    iSciencePeer-reviewedCC BY 4.0Molecular biology & gene regulationCell biologyCrossrefCell Press
  4. Sleep as Obligate Phenotypic Switching: An Ultimate Explanation for Temporal Niche Partitioning
    Andrew Freiberg
    EcoEvoRxivPreprintCC BY 4.0Full textEcologyEcoEvoRxiv
  5. Stochastic gene expression drives state switching and phenotypic heterogeneity in RNA repair
    H. J. Hindley, R. Lara Molina, A. Y. Weisse
    bioRxivPreprintCC BY-NCFull textBioinformatics & computational biologybioRxiv

Cite

BibTeXRIS
BibTeX
@article{yao2026cxcl16,
  title = {{CXCL16 promotes macrophage-driven inflammation and vascular smooth muscle cell phenotypic switching during carotid plaque destabilization}},
  author = {Guoqing Yao and Tiankuo Luan and Daqiang Song and Guojing Liu and Xuemei Hu and Yangyang Feng and Rui Liang and Yu Zhao and H LIU},
  journal = {International Immunopharmacology},
  year = {2026},
  month = may,
  doi = {10.1016/j.intimp.2026.116848},
  url = {https://doi.org/10.1016/j.intimp.2026.116848},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - CXCL16 promotes macrophage-driven inflammation and vascular smooth muscle cell phenotypic switching during carotid plaque destabilization
AU  - Guoqing Yao
AU  - Tiankuo Luan
AU  - Daqiang Song
AU  - Guojing Liu
AU  - Xuemei Hu
AU  - Yangyang Feng
AU  - Rui Liang
AU  - Yu Zhao
AU  - H LIU
PY  - 2026
DA  - 2026/05/18
JO  - International Immunopharmacology
DO  - 10.1016/j.intimp.2026.116848
UR  - https://doi.org/10.1016/j.intimp.2026.116848
AB  - Carotid plaque instability is a major determinant of ischemic stroke and is characterized by heightened inflammation and structural remodeling of the vessel wall. Although macrophages and vascular smooth muscle cells (VSMCs) are central to plaque vulnerability, the mechanisms coordinating immune activation with vascular remodeling remain incompletely understood. Bulk transcriptomic data from multiple Gene Expression Omnibus (GEO) datasets were integrated to compare unstable and stable carotid plaques. Differential gene expression analysis, weighted gene co-expression network analysis, immune-gene curation, and machine learning methods (least absolute shrinkage and selection operator [LASSO] and random forest) were used to identify key genes and construct a nomogram. The findings were validated using independent datasets, single-cell RNA sequencing, and human carotid plaque specimens. The mechanistic roles of CXCL16 were examined using macrophage functional assays, NF-κB inhibition, VSMC co-culture with macrophage-conditioned media, and the establishment of an ApoE −/− carotid atherosclerosis model with local CXCL16 suppression. Cell-cell communication and pseudotime analyses were performed to explore macrophage-VSMC interactions. CXCL16 , CCL2 , and MMP9 were consistently upregulated in unstable plaques and showed robust diagnostic performance across datasets. A three-gene nomogram generated from this study suggested potential clinical utility. Single-cell analyses indicated that CXCL16 was enriched in plaque-associated M1 macrophages and was associated with inflammatory activation states. Human plaque staining confirmed higher CXCL16/CCL2/MMP9 expression in unstable plaques with increased macrophage and leukocyte infiltration. In vitro, CXCL16 knockdown attenuated NF-κB activation and reduced downstream inflammatory mediators (including CCL2), accompanied by decreased macrophage migration; NF-κB inhibition phenocopied these effects. In vivo, CXCL16 suppression reduced carotid plaque formation and inflammatory cell infiltration. Cell-cell communication analysis revealed enhanced SPP1/osteopontin signaling from M1 macrophages toward VSMCs, with higher SPP1 expression in CXCL16-high M1 macrophages. Co-culture experiments showed that macrophage-derived CXCL16 promoted VSMC migration and phenotypic switching, which was reversed by CXCL16 knockdown. CXCL16 acts as a central inflammatory mediator in carotid plaque destabilization by promoting NF-κB–dependent macrophage activation and migration. It also enhances SPP1/osteopontin-associated macrophage-VSMC crosstalk that drives phenotypic remodeling in VSMCs. Our results collectively suggest CXCL16 as a diagnostic biomarker and a potential therapeutic target for carotid atherosclerosis. • CXCL16 drives carotid plaque destabilization by promoting macrophage inflammation and VSMC switching. • Transcriptomic and single-cell analyses highlight CXCL16 as a key inflammatory mediator in plaque instability. • CXCL16 suppression reduces macrophage activation and VSMC migration, suggesting a therapeutic target.
SN  - 1567-5769
SN  - 1878-1705
ER  -