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Single-cell RNA sequencing reveals B cell-T cell interactions in vascular adventitia of homocysteinemia-accelerated atherosclerosis

ABSTRACT: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. However, a comprehensive understanding of immune cells in HHcy-accelerated atherosclerotic aortas (HHcy-AA) and the underlying mechanisms are still lacking. In this study, single-cell RNA sequencing (scRNA-seq) analysis of aortas from three atherosclerotic models on ApoE-/- mice revealed 15 distinct immune cell clusters. Among them, B cells showed the most significant increase in the vessels of HHcy ApoE-/- mice compared with those in ApoE-/- mice fed a chow diet or western diet (WD). Further cell-cell contact reanalyses revealed that B cells, but not dendritic cells or macrophages, played a dominant role in the class II major histocompatibility complex (MHCII) signaling in HHcy-AA. Mechanistically, Hcy induced the nuclear translocation of pyruvate kinase M2 (PKM2) in B cells. Nuclear PKM2 interacted with and phosphorylated cyclic AMP-responsive element-binding protein 1 (CREB1), and then PKM2-CREB1 complex bound to promoter III of Ciita, a master transactivator of MHCII, and further induced MHCII expression. Adoptive transfer experiments demonstrated that nuclear PKM2-regulated B cell antigen presentation is essential for B cell-mediated T cell activation and atherogenesis. In summary, our study provides a comprehensive immune cell atlas of HHcy-AA, which is distinct with those in WD-fed ApoE-/- mice. MHCII-related antigen presentation may be the main function of aortic B cells. We also provide a novel perspective for the intervention in early development of atherosclerosis via the PKM2-CREB1-CIITA-MHCII axis in B cells, especially for HHcy-accelerated vascular inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE190220 | GEO | 2021/12/08

REPOSITORIES: GEO

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