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

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).

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.

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.