Efferocytic Defects in Early Atherosclerosis Are Driven by GATA2 Overexpression in Macrophages.

Charles Yin,Lillian Barra,Emily N Pawlak,Angela M Vrieze,Neha Sharma,Jonathan Hu,James Akingbasote,Jimmy D Dikeakos,A Dave Nagpal,Bryan Heit,Mara Rosoga,Rajesh Abraham Jacob

doi:10.3389/fimmu.2020.594136

Efferocytic Defects in Early Atherosclerosis Are Driven by GATA2 Overexpression in Macrophages.

Charles Yin, Lillian Barra + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2020.594136

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Abstract

The loss of efferocytosis—the phagocytic clearance of apoptotic cells—is an initiating event in atherosclerotic plaque formation. While the loss of macrophage efferocytosis is a prerequisite for advanced plaque formation, the transcriptional and cellular events in the pre-lesion site that drive these defects are poorly defined. Transcriptomic analysis of macrophages recovered from early-stage human atherosclerotic lesions identified a 50-fold increase in the expression of GATA2, a transcription factor whose expression is normally restricted to the hematopoietic compartment. GATA2 overexpression in vitro recapitulated many of the functional defects reported in patient macrophages, including deficits at multiple stages in the efferocytic process. These findings included defects in the uptake of apoptotic cells, efferosome maturation, and in phagolysosome function. These efferocytic defects were a product of GATA2-driven alterations in the expression of key regulatory proteins, including Src-family kinases, Rab7 and components of both the vacuolar ATPase and NADPH oxidase complexes. In summary, these data identify a mechanism by which efferocytic capacity is lost in the early stages of plaque formation, thus setting the stage for the accumulation of uncleared apoptotic cells that comprise the bulk of atherosclerotic plaques.

Highlights

Macrophages are the primary immune cell type driving the initiation and progression of atherosclerosis
Gene ontology-based clustering and gene set enrichment analysis were used to identify biological processes that may be perturbed in these intimainfiltrating macrophage (IIM), identifying putative defects in cholesterol homeostasis, the pathways used to engulf and degrade pathogens and apoptotic cells, and antigen processing (Figure S3)
Of the transcription factors upregulate in IIMs, only GATA2 had been previously implicated in coronary artery disease in humans [54,55,56]

Summary

Introduction

Macrophages are the primary immune cell type driving the initiation and progression of atherosclerosis. Under homeostatic conditions macrophages are atheroprotective, through both the endocytic clearance of lipoprotein deposits and through efferocytosis—the phagocytic clearance of apoptotic cells. Combined, these processes prevent the accumulation of lipids and apoptotic cells, as well as induce anti-inflammatory signaling, thereby countering the major pathological processes required for plaque formation [1,2,3,4]. As atherosclerosis progresses, macrophage efferocytosis within the lesion becomes defective, leaving apoptotic foam cells uncleared These apoptotic cells eventually undergo secondary necrosis, releasing pro-inflammatory alarmins and generating the necrotic core of the plaque [15,16,17]. Lysosomal proteins released during necrosis further destabilize the plaque, contributing to plaque rupture and exposure of thrombogenic factors contained within the plaque, resulting in thrombus formation that may lead to a stroke or myocardial infarct [15, 20, 21]

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