Complement C3/C3a-CCL9 feedback loop orchestrates inflammatory crosstalk to accelerate aortic dissection.

Aortic dissection (AD) is a life-threatening vascular disease marked by severe inflammation and immune cell infiltration. While complement activation has been implicated, the specific roles of complement component 3 (C3) and its active fragment C3a in AD pathogenesis remain unclear. In our study, C3/C3a levels were determined in plasma and aortic tissues from AD patients and β-aminopropionitrile-induced AD mice. Despite unchanged C3 levels, plasma C3a was markedly elevated and deposited in the aortic wall. The origin of C3a was traced using bone marrow-derived macrophages, identifying macrophages as the predominant source. Transcriptomic profiling and expressional validation of C3a-stimulated vascular smooth muscle cells (VSMCs) identified chemokine (C-C motif) ligand 9 (CCL9) as a downstream effector. Functional assays demonstrated that C3a recruited macrophages through C3a receptor (C3aR) and induced phenotypic switching of VSMCs toward a synthetic, pro-inflammatory state with increased CCL9 secretion. CCL9, in turn, promoted macrophage recruitment and activation via C-C chemokine receptor type 1 (CCR1) and augmented C3 synthesis, establishing a self-perpetuating inflammatory circuit. The C3 cleavage inhibitor Compstatin analog CP40 with two additional lysines at the C-terminus (CP40KK) was tested in vivo, showing that pharmacological blockade of C3 activation attenuated C3a and CCL9 expression, reduced macrophage infiltration, preserved aortic wall integrity, and improved survival outcomes in AD mice. In conclusion, we identified a C3/C3a-CCL9 feedback loop as a key driver of AD progression. This study highlights VSMCs as active regulators of vascular inflammation and positions C3a and CCL9 as potential therapeutic targets for AD intervention.