2. Academic Validation
  3. Inhibition of aortic CX3CR1+ macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice

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.
Jiaqi Huang 1,  Hao Liu 2,  Zhujiang Liu 1,  Zhenting Wang 3,  Hanshi Xu 3,  Zhuofan Li 1,  Shan Huang 4,  Xueyuan Yang 1,  Yicong Shen 1,  Fang Yu 1,  Yulin Li 4,  Junming Zhu 2,  Wei Li 5,  Li Wang 3,  Wei Kong 1,  Yi Fu 1
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 2 Department of Cardiovascular Surgery, Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Engineering Research Center of Vascular Prostheses, Beijing, China.
  • 3 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
  • 5 Department of Vascular Surgery, Peking University People's Hospital, Beijing, China.
PMID: 39817456 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.

Figures
Products