Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

SPP1high fibrogenic macrophages mediate protective fibrotic remodeling and promote vascular stability in hypertension-associated aortic dissection.

Abstract

BACKGROUND: Hypertension-associated aortic dissection (HTN-AD) features intense immune activation and extracellular matrix disruption, yet the cellular programs that promote aortic-wall stabilization remain unclear. We aimed to identify macrophage states associated with vascular integrity and to determine whether these states could be mechanistically or therapeutically leveraged. METHODS: Single-cell RNA sequencing was performed on thoracic aortas from HTN-AD, Marfan syndrome-associated AD, and donor controls (n = 3 per group). Peripheral and tear-adjacent blood samples were analyzed in patients with HTN-AD, MS-AD, and healthy donors (n = 30 per group), with paired intraoperative tear-adjacent sampling performed when available (n = 10). Circulating monocytes and serum cytokines were profiled by flow cytometry and ELISA. Functional validation included TGF-beta1 conditioning of human monocytes and murine macrophages and adoptive transfer experiments in a murine AD model. RESULTS: A distinct SPP1high fibrogenic macrophage population was enriched in diseased aortas and transcriptionally bridged low-inflammatory macrophages and matrix-active states. Patients with HTN-AD displayed increased tear-adjacent non-classical monocytes and higher monocytic SPP1, correlating with serum TGF-beta1 and a shorter ICU stay. TGF-beta1 induced an SPP1-dependent fibrogenic program in macrophages while suppressing inflammatory markers. Myeloid Spp1 deficiency aggravated aortic dilatation and wall disruption, whereas adoptive transfer of TGF-beta1-conditioned SPP1high macrophages reduced false lumen formation, improved collagen organization, decreased IL-1beta and IL-6 expression, and enhanced survival. CONCLUSIONS: A TGF-beta1-SPP1 axis drives the emergence of SPP1high fibrogenic macrophages that support structural stabilization of the dissected aorta. Targeting this reparative myeloid program may offer a mechanistically informed therapeutic strategy for acute aortic syndromes.