Inhibition of aortic CX3CR1+ macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice

J Clin Invest. 2025 Jan 16;135(2):e178198. doi: 10.1172/JCI178198.

Abstract

The pathogenesis of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is generally attributed to vascular smooth muscle cell (VSMC) pathologies. However, the role of immune cell-mediated inflammation remains elusive. Single-cell RNA sequencing identified a subset of CX3CR1+ macrophages mainly located in the intima in the aortic roots and ascending aortas of Fbn1C1041G/+ mice, further validated in MFS patients. Specific elimination of CX3CR1+ cells by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression. Administering the monoclonal antibodies to respectively neutralize TNF-α and IGF1 produced by CX3CR1+ cells from MFS patients greatly suppressed the cocultured MFS patient-specific induced pluripotent stem cell-derived VSMC inflammation. BM transplantation and parabiosis revealed that CX3CR1+ macrophages are mainly originated from BM-derived monocytes. Targeting TNF-α and IGF1 in CX3CR1+ macrophages via shRNA lentivirus transduction in BM cells efficiently suppressed TAA development in BM-transplanted Fbn1C1041G/+ mice. Application of the CCR2 antagonist RS504393 to inhibit monocyte infiltration markedly reduced the accumulation of CX3CR1+ macrophages and subsequently alleviated TAA progression in Fbn1C1041G/+ mice. In summary, CX3CR1+ macrophages mainly located in aortic intima mediate TAA formation by paracrinally causing VSMC inflammation, and targeting them offers a potential antiinflammatory therapeutic strategy for MFS-related TAA.

Keywords: Cardiovascular disease; Inflammation; Macrophages; Vascular biology.

MeSH terms

  • Adipokines
  • Animals
  • Aortic Aneurysm, Thoracic* / genetics
  • Aortic Aneurysm, Thoracic* / immunology
  • Aortic Aneurysm, Thoracic* / metabolism
  • Aortic Aneurysm, Thoracic* / pathology
  • CX3C Chemokine Receptor 1* / genetics
  • CX3C Chemokine Receptor 1* / immunology
  • CX3C Chemokine Receptor 1* / metabolism
  • Disease Progression
  • Fibrillin-1 / genetics
  • Humans
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / immunology
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Male
  • Marfan Syndrome* / genetics
  • Marfan Syndrome* / immunology
  • Marfan Syndrome* / metabolism
  • Marfan Syndrome* / pathology
  • Mice
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / pathology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Insulin-Like Growth Factor I
  • Tumor Necrosis Factor-alpha
  • CX3CR1 protein, human
  • Fibrillin-1
  • insulin-like growth factor-1, mouse
  • Fbn1 protein, mouse
  • Adipokines