The MCP-1/CCR2–CD16⁺ monocyte axis drives thrombus fibrosis in Chronic Thromboembolic Pulmonary Hypertension

OBJECTIVE: This study aimed to determine whether dysregulation of the MCP-1/CCR2 axis and expansion of CD16⁺ monocytes represent a mechanistic link between acute pulmonary embolism (APE) and the chronic fibrotic vascular occlusion characteristic of chronic thromboembolic pulmonary hypertension (CTEPH). APPROACH AND RESULTS: We performed an integrative multi-level analysis combining multicenter clinical cohorts, single-cell transcriptomics, and in vivo modeling. In a multicenter cohort (32 CTEPH patients and 20 healthy controls), circulating CD16⁺ monocytes were selectively expanded in CTEPH and correlated with disease severity, as assessed by pulmonary vascular resistance and mean pulmonary arterial pressure. MCP-1 levels were significantly elevated and positively associated with CD16⁺ monocyte expansion. Single-cell RNA sequencing of human APE thrombi (5 patients; 24,399 cells) revealed that CD16⁺ monocytes exhibit a profibrotic transcriptional program and function as key signaling hubs within CCL-mediated communication networks. Histological analysis further demonstrated spatial colocalization of MCP-1 expression and M2 macrophage infiltration in fibrotic thrombus regions. In a murine model of venous thrombosis recapitulating fibrotic thrombus remodeling, CCR2 inhibition with RS102895 suppressed the expansion of profibrotic monocytes, reduced M2 macrophage infiltration, and attenuated thrombus fibrosis. CONCLUSION: These findings identify the MCP-1/CCR2-CD16⁺ monocyte axis as a central driver of fibrotic thrombus remodeling in CTEPH and provide a mechanistic framework linking acute thrombosis to chronic vascular occlusion. Targeting this pathway may represent a promising immunomodulatory strategy to limit pathological vascular remodeling.