The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity

Abstract

Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling. However, persistent inflammation could be detrimental to the heart. Studies suggest that cardiac inflammation and tissue repair needs to be tightly regulated such that the timely resolution of the inflammation may prevent adverse cardiac damage. This involves the recognition of damage; activation and release of soluble mediators such as cytokines, chemokines, and proteases; and immune cells such as monocytes, macrophages, and neutrophils. This is important in the context of doxorubicin-induced cardiotoxicity as well. Doxorubicin (Dox) is an effective chemotherapy against multiple cancers but at the cost of cardiotoxicity. The innate immune system has emerged as a contributor to exacerbate the disease. In this review, we discuss the current understanding of the role of innate immunity in the pathogenesis of cardiovascular disease and dox-induced cardiotoxicity and provide potential therapeutic targets to alleviate the damage.

Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy

“…The infiltration and activation of neutrophils contribute to DIC [ 10 ], and pharmacological inhibition of neutrophils significantly prevents the cardiotoxic effects of DOX [ 11 ]. The acute inflammatory response to DOX is associated with the apoptosis of monocytes and macrophages [ 12 , 13 ]. DOX treatment disrupts the cardiac M1/M2 macrophage balance and suppresses M2 macrophage differentiation [ 14 ], which plays a critical role in cardiac injury and repair.…”

Analysis and Validation of Critical Signatures and Immune Cell Infiltration Characteristics in Doxorubicin-Induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning

“…Recent evidence has shown that immune cells play a critical role in the pathophysiological process of DIC. 6 , 32 , 33 Therefore, we investigated the link between key features in DIC and immune infiltration. The swatches of different groups are well divided in the training set in PCA ( Figure 7A ).…”

B-Cell Immune Checkpoints Come of Age in Cardio-oncology

“…8,9 Inflammatory cytokines, likely derived from macrophages or monocytes, such as IFN-γ (interferon-gamma), TNF (tumor necrosis factor), and IL-1β (interleukin-1β) have also been shown to contribute to doxorubicin mediated apoptosis. 10 In this issue of Circulation Research, the authors explored the role of adaptive immunity, and specifically B-cells, in the cardioprotective effects conferred by exercise against DIC. Compared with sedentary mice, mice that were conditioned with exercise before doxorubicin administration curtailed cardiac fibrosis, cardiomyocyte apoptosis, and improved left ventricular ejection fraction.…”