Role of Neutrophils in Cardiac Injury and Repair Following Myocardial Infarction

Abstract

Neutrophils are first-line responders of the innate immune system. Following myocardial infarction (MI), neutrophils are quickly recruited to the ischemic region, where they initiate the inflammatory response, aiming at cleaning up dead cell debris. However, excessive accumulation and/or delayed removal of neutrophils are deleterious. Neutrophils can promote myocardial injury by releasing reactive oxygen species, granular components, and pro-inflammatory mediators. More recent studies have revealed that neutrophils are able to form extracellular traps (NETs) and produce extracellular vesicles (EVs) to aggravate inflammation and cardiac injury. On the contrary, there is growing evidence showing that neutrophils also exert anti-inflammatory, pro-angiogenic, and pro-reparative effects, thus facilitating inflammation resolution and cardiac repair. In this review, we summarize the current knowledge on neutrophils’ detrimental roles, highlighting the role of recently recognized NETs and EVs, followed by a discussion of their beneficial effects and molecular mechanisms in post-MI cardiac remodeling. In addition, emerging concepts about neutrophil diversity and their modulation of adaptive immunity are discussed.

Leukocyte-Mediated Cardiac Repair after Myocardial Infarction in Non-Regenerative vs. Regenerative Systems

“…Once mobilized to the wound or site of infection, neutrophils ingest cellular debris and invading pathogens by phagocytosis. These leukocytes also release their granular enzymes such as myeloperoxidase and matrix metalloproteases (MMPs) during degranulation for additional antimicrobial and tissue repair/remodeling activity, respectively [60,61,158]. Another critical host defense mechanism provided by neutrophils derives from their formation of neutrophil extracellular traps (NETs), which are composed of chromatin filaments with granular proteins that can obstruct and bind pathogens [158].…”

“…Timing: Days 1-14, peak 3 days with permanent ligation; days 1-7, peak day 1 with reperfusion [57,58]. Detrimental: CM death and adverse cardiac remodeling [59][60][61].…”

“…Beneficial: Clear dead cells/debris, angiogenesis, inflammation resolution [60]; reparative macrophage polarization [62].…”

Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases

“…Galectin-3, which predominantly modulates cell-ECM interactions, acts as a late responder and increases at the subacute stage for remodelling [ 13 ]. By employing peptidylarginine deiminase 4, the formation of neutrophil extracellular traps through chromatin filaments, in conjunction with granular and cytoplasmic components and extracellular vesicles, has been proposed to worsen cardiac inflammation and injury [ 14 ]. Fibroblasts were the third player to orchestrate the inflammatory status heralded by MI.…”

ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress

“…However, excessive accumulation and/or delayed switch from these proinflammatory cells infiltration to reparative inflammatory cells (such as CD206 + macrophages) has detrimental effects. By releasing reactive oxygen species, granular components, and proinflammatory mediators such as tumor necrosis factor-alpha (TNFα), soluble interleukin-6 receptor (sIL-6R), and CXC chemokine receptor 2 (CXCR2), neutrophils and macrophages contribute to adverse myocardial injury and remodeling ( Adu-Amankwaah et al, 2021a ; Ma, 2021 ). Additionally, the activation of T and B lymphocytes by dendritic cells has been shown to play crucial roles in myocardial inflammation ( Santos-Zas et al, 2018 ; Santos-Zas et al, 2021 ).…”