Biology subjects

Vrieze, A. M.

Publications and source records attributed to Vrieze, A. M..

3 recordsLinked to original sources

bioRxiv2025

GATA2 Induces a Stem Cell-Like Transcriptional Program in Macrophages that Promotes Atherogenesis.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden necrotic macrophages within blood vessels walls. GATA2 is a normally hematopoietic transcription factor which in the bone marrow helps maintain the proliferative, non-differentiated phenotype of hematopoietic progenitors. Unexpectedly, GATA2 is upregulated in macrophages within atherosclerotic plaque, where it plays an unknown role in disease progression. Although GATA2 can be expressed from two promoters, we determined that the atherogenic stimuli oxidized low-density lipoprotein and TNF induce GATA2 expression via the internal (IG) GATA2 promoter, with GATA2 transcription initiated by the transcription factors NF-{kappa}B, STAT1, and the aryl hydrocarbon receptor. GATA2 had a divergent effect on promoter activity, with GATA2 upregulating genes associated with stem cell maintenance, proliferation, reactive oxygen species production, and migration, while downregulating genes central to macrophage function including those for cholesterol efflux, pathogen phagocytosis, and for the efferocytosis of apoptotic cells. Consequentially, GATA2-expressing macrophages had a pro-atherogenic phenotype typified by an invasive phenotype, poor cholesterol efflux, and impaired phagocytosis and efferocytosis. These results indicate that GATA2 upregulation induces an immature, stem cell-like phenotype in atheroma macrophages, thereby promoting plaque cellularity while compromising atheroprotective mechanisms such as cholesterol clearance and apoptotic cell removal.

immunology↗

bioRxiv2025

GATA2 Mediates Macrophage Proliferation During Atherosclerosis

Atherosclerosis is fueled by the buildup of lipid-laden macrophages within the vascular intima. These macrophages are derived from monocytes that are recruited from the circulation into the developing lesion, where they proliferate and differentiate into macrophages, with proliferation producing most of the macrophages in the resulting lesions. However, the signals and transcriptional events driving the proliferation of atherosclerotic plaque macrophages remain poorly understood. Analysis of human plaque spanning a range of disease severity identified a subpopulation of macrophages that expressed the hematopoietic transcription factor GATA2. These GATA2-expressing macrophages had a transcriptional profile that was intermediary between monocytes and mature macrophages, and selectively upregulated genes associated with proliferation and apoptosis. The expression of GATA2 was concomitant with plaque macrophage proliferation at all stages of disease, with over 90% of proliferating macrophages expressing GATA2. GATA2 was upregulated in macrophages following exposure to oxLDL, with GATA2 expression being necessary and sufficient for the proliferation of these macrophages. In these cells, GATA2 mediates proliferation by upregulating expression of the proto-oncogene MYB, while simultaneously decreasing sensitivity to apoptosis induced by the unfolded protein response. Together, these data identify GATA2 as a transcription factor upregulated by atherogenic stimuli that functions as the primary mediator of macrophage proliferation in atherosclerotic plaque.

immunology↗

bioRxiv2023

SARS-CoV-2 NSP5 Antagonizes the MHC II Antigen Presentation Pathway by Hijacking Histone Deacetylase 2

SARS-CoV-2 interferes with antigen presentation by downregulating MHC II on antigen presenting cells, but the mechanism mediating this process is unelucidated. Herein, analysis of protein and gene expression in human antigen presenting cells reveals that MHC II is downregulated by the SARS-CoV-2 main protease, NSP5. This suppression of MHC II expression occurs via decreased expression of the MHC II regulatory protein CIITA. This downregulation of CIITA is independent of NSP5s proteolytic activity, but rather, NSP5 delivers HDAC2 to IRF3 at an IRF binding site within the CIITA promoter. Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a mechanism by which SARS-CoV-2 limits MHC II expression, thereby delaying or weakening the subsequent adaptive immune response. ImportanceSARS-CoV-2 alters the expression of many immunoregulatory proteins to limit and delay the host antiviral response, thereby producing a more severe and longer-lasting infection. Preventing and limiting the activation of helper T cells by reducing MHC II expression on antigen presenting cells is one of these strategies, but while this mechanism was identified early in the pandemic, the mechanism allowing SARS-CoV-2 to limit MHC II expression has remained unclear. Herein, we demonstrate that this occurs via a tripartite interaction between viral NSP5 and host HDAC2 and IRF3, where a complex of NSP5 and HDAC2 is recruited to IRF3 bound to the promoter of CIITA--the master regulator of MHC II expression--with the delivery of HDAC2 then mediating the deacetylation of the CIITA promoter and the suppression of MHC II expression.

immunology↗