Immune Mechanisms of Plaque Instability

Abstract

Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed.

Guanmaitong Granule Attenuates Atherosclerosis by Inhibiting Inflammatory Immune Response in ApoE−/− Mice Fed High-Fat Diet

“…37 The inflammatory response is involved in all stages of AS development. 39 CANTOS experiment confirmed the correctness of AS inflammation theory and opened the second era of AS prevention and treatment. It focused on anti-inflammatory benefits.…”

Enhanced Local Delivery of microRNA-145a-5P into Mouse Aorta via Ultrasound-Targeted Microbubble Destruction Inhibits Atherosclerotic Plaque Formation

“…One limitation of our work is the use of ApoE–/– mice fed a Western diet as an AS model; the unstable plaques are not properly mimicked by this “classic” mouse model. − The rupture of unstable plaques and thrombosis are the main factors leading to heart attacks and strokes. , It has been suggested that this might be because of the tiny diameter of the mouse vessels. As the vessel diameter decreases, the surface tension increases exponentially, thereby reducing the possibility of plaque rupture …”

“…52−54 The rupture of unstable plaques and thrombosis are the main factors leading to heart attacks and strokes. 54,55 It has been suggested that this might be because of the tiny diameter of the mouse vessels. As the vessel diameter decreases, the surface tension increases exponentially, thereby reducing the possibility of plaque rupture.…”

Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas ofLdlr-/-mice

“…Indeed, a crucial role of activated neutrophils in the formation of unstable plaques via uncontrolled release of ROS, cytotoxic granules, matrix degrading enzymes, etc., has been demonstrated in several papers. 27 However, very little is known about mechanisms of neutrophil recruitment into the atherosclerotic aorta. To address the role of STAT4 in neutrophil migration to sites of atherosclerosis, we analyzed several aspects of neutrophil migration both in vitro and in vivo .…”