Inhibition of Intimal CX3CR1+ Macrophages Mitigates Thoracic Aortic Aneurysm Progression in Marfan Syndrome
Current understanding on the pathogenesis of thoracic aortic aneurysms (TAAs) in Marfan Syndrome (MFS) mainly focuses on vascular smooth muscle cell (VSMC) pathologies. Whether immune cell-mediated inflammation drives the progression of TAAs is still elusive. Using single-cell RNA sequencing, a subset of macrophages highly expressing CX3CR1 and mainly locating in the aortic intima was identified in aortic root and ascending aortas from Fbn1C1041G/+ mice, and further validated in MFS patients. Specific elimination of CX3CR1+ macrophages by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression, suggesting their pathogenic action. Using monoclonal antibodies Adalimumab and Teprotumumab to respectively neutralize the proinflammatory cytokines TNFalpha and IGF1 produced by CX3CR1+ macrophages from MFS patients substantially suppressed CX3CR1+ macrophage-mediated inflammation in MFS patient-specific induced pluripotent stem cell (iPSC)-derived VSMCs. Furthermore, bone marrow transplantation and parabiosis using Cx3cr1GFP/+ mice revealed the intimal CX3CR1+ macrophages derived from circulating monocytes. Administration of CCR2 antagonist RS504393 to inhibit monocyte infiltration significantly reduced intimal CX3CR1+ macrophages and subsequently alleviated TAA development in Fbn1C1041G/+ mice. In conclusion, intimal CX3CR1+ macrophages mediated TAA formation through paracrinally causing VSMC inflammation. Targeting intimal CX3CR1+ macrophages would be a promising anti-inflammatory strategy in TAA therapy for MFS. Overall design: Single cell suspensions of aortic root and ascending aortas from WT (N = 6) and Fbn1C1041G/+ (N = 6) mice