Macrophage-derived TNF-α promotes vascular inflammation and cell crosstalk in human atherosclerotic plaques via TNFRSF1A.

Authors

Tao Wang, Changtian Hu, Henglei Xia, Jianfeng Hao, Bing Li, Liza Gutierrez, Fei Lu, Tingting Yu, Chuanqing Yu, Congxia Chen, Shuyang Dong, Xiuqun Gong, Min Xue, Peixiang Yang, Wei Huang, Xinrong Tao, Ting Li, Adnan H Siddiqui, Mei Zhang

Published in

Atherosclerosis. Volume 422. Pages 121924. Oct 10, 2026. Epub Oct 10, 2026.

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease driven by complex cellular crosstalk within plaques. How a key inflammatory pathway orchestrates multicellular vascular injury and whether this is conserved across vascular beds remains incompletely understood.
Carotid and coronary plaques were profiled by single-cell RNA sequencing and spatial transcriptomics. Immunofluorescence validated cell localization and TNF-TNFRSF1A signaling, and CellChat analyzed intercellular communication. THP-1 macrophages were subjected to hypoxia/nutrient deprivation or ox-LDL, and conditioned media were applied to endothelial and smooth muscle cells to assess TNFRSF1A-dependent cytotoxicity, NF-κB/MAPK activation, lipid accumulation, and cytokine release.
Single-cell and spatial analyses revealed a conserved plaque architecture: myeloid cells enriched in the lipid core, mural and endothelial cells at the periphery. Five endothelial, eight mural, and six macrophage subtypes showed distinct spatial and functional features. Central to these interactions, TNF-TNFRSF1A emerged as a central signaling axis linking macrophages, endothelial cells, and smooth muscle cells. Microenvironmental stress amplified macrophage TNF-α secretion, leading to promoting TNFRSF1A-dependent vascular cell death, NF-κB/MAPK activation, and foam cell formation. Mechanistically, ox-LDL upregulated increased macrophage CD36 and TREM2, while TNFRSF1A knockdown mitigated lipid accumulation, cytokine release, and downstream signaling.
These findings delineate the spatial and functional landscape of AS plaques and reveal a conserved, spatially constrained mechanism: macrophage-derived TNF-α drives TNFRSF1A-dependent vascular injury, inflammatory amplification, and foam cell formation, highlighting this axis as a promising therapeutic target for atherosclerotic diseases.

PMID:
42913050
Bibliographic data and abstract were imported from PubMed on 24 Oct 2026.

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