Interplay Between KLF4, STAT, IRF, and NF-κB in VSMC and Macrophage Plasticity During Vascular Inflammation and Atherosclerosis

Int J Mol Sci. 2025 Oct 20;26(20):10205. doi: 10.3390/ijms262010205.

Abstract

Atherosclerosis is characterized by atherosclerotic plaque formation in large and medium vessels, mediated by endothelial cell (EC) dysfunction, altered contractility of Vascular Smooth Muscle Cells (VSMCs) and recruitment of blood leukocytes to the injured vascular endothelium. These include macrophages (MØ), T lymphocytes, and dendritic cells, which drive the production of many inflammatory mediators and the process of chronic inflammation. Also, de-differentiation or phenotypic switching of VSMCs contributes to vascular remodeling and the pathogenesis of atherosclerosis. Likewise, MØ plasticity and the presence of different phenotypes have a major effect on atherosclerotic plaque formation. The multi-functional transcriptional regulator and pluripotency factor Krüppel-like factor 4 (KLF4) acts as a gatekeeper of VSMC phenotypic switching and MØ polarization during vascular inflammation and atherosclerosis. Similarly, pro-inflammatory pathways activated by Toll-like receptor (TLR)4 and Interferon gamma (IFNγ) emerge as key components of VSMC and MØ plasticity, tightly regulated by Signal Transducer and Activator of Transcription (STAT)s, Interferon Regulatory Factor (IRF)s, and Nuclear factor-κB (NF-κB). Recent discoveries predict a collaborative role of these transcription factors in different transcriptional mechanisms connected to inflammation and atherosclerosis. This review provides novel insight into the transcriptional regulatory interplay between KLF4, STATs, IRFs, and NF-κB in VSMC phenotypic switching and MØ polarization during atherogenesis. Detailed understanding of these transcriptional networks will enable us to develop novel diagnostic and therapeutic strategies to combat vascular proliferative diseases, including atherosclerosis.

Keywords: Interferon Regulatory Factor (IRF); Interferon gamma (IFNγ) and Toll-like receptor (TLR)4 signaling; Krüppel-like factor 4 (KLF4); Nuclear factor-κB (NF-κB); Signal Transducer and Activator of Transcription (STAT); Vascular Smooth Muscle Cell (VSMC) and macrophage plasticity; atherosclerosis; transcriptional networks.

Publication types

  • Review

MeSH terms

  • Animals
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Cell Plasticity
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interferon Regulatory Factors* / metabolism
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors* / metabolism
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Muscle, Smooth, Vascular* / metabolism
  • Muscle, Smooth, Vascular* / pathology
  • Myocytes, Smooth Muscle* / metabolism
  • Myocytes, Smooth Muscle* / pathology
  • NF-kappa B* / metabolism
  • STAT Transcription Factors* / metabolism
  • Signal Transduction

Substances

  • Kruppel-Like Factor 4
  • KLF4 protein, human
  • NF-kappa B
  • Kruppel-Like Transcription Factors
  • Interferon Regulatory Factors
  • STAT Transcription Factors