Inhibition of aortic CX3CR1+ macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice
Jiaqi Huang, Hao Liu, Zhujiang Liu, Zhenting Wang, Hanshi Xu, Zhuofan Li, Shan Huang, Xueyuan Yang, Yicong Shen, Fang Yu, Yulin Li, Junming Zhu, Wei Li, Li Wang, Wei Kong, Yi Fu
Jiaqi Huang, Hao Liu, Zhujiang Liu, Zhenting Wang, Hanshi Xu, Zhuofan Li, Shan Huang, Xueyuan Yang, Yicong Shen, Fang Yu, Yulin Li, Junming Zhu, Wei Li, Li Wang, Wei Kong, Yi Fu
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Research Article Inflammation Vascular biology

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

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.

Authors

Jiaqi Huang, Hao Liu, Zhujiang Liu, Zhenting Wang, Hanshi Xu, Zhuofan Li, Shan Huang, Xueyuan Yang, Yicong Shen, Fang Yu, Yulin Li, Junming Zhu, Wei Li, Li Wang, Wei Kong, Yi Fu

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Figure 4

TNF-α– and IGF1-mediated intimal CX3CR1+ macrophage-caused VSMC inflammation.

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TNF-α– and IGF1-mediated intimal CX3CR1+ macrophage-caused VSMC inflamma...
(A) The experimental workflow of the evaluation of gene expression in MFS patient-specific iPSC-derived VSMCs with 24-hour treatment of conditioned media produced from 48-hour cultures of MFS patient-derived CX3CR1+ and CX3CR1– macrophages. (B) Real-time PCR of gene expression in MFS patient-specific iPSC-derived VSMCs with conditioned media treatment. n = 4. *P < 0.05 by unpaired Student’s t test. (C and D) Real-time PCR of gene expression in MFS patient-specific iPSC-derived VSMCs with conditional media treatment in the presence of adalimumab (10 μg/mL) or IgG. n = 4. *P < 0.05 by 2-way ANOVA followed by Tukey’s test for post hoc comparison. (E and F) Real-time PCR of gene expression in MFS patient-specific iPSC-derived VSMCs with conditioned media treatment in the presence of teprotumumab (200 μg/mL) or IgG. n = 4. *P < 0.05 by 2-way ANOVA followed by Tukey’s test for post hoc comparison. (G) Real-time PCR of gene expression in the aortic root and ascending aortas from 21-week-old Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice with or without DT-mediated depletion. n = 4. *P < 0.05 by unpaired Student’s t test.