Abstract
Myocarditis is a life-threatening inflammatory disorder that affects the cardiac muscle tissue. Current treatments merely regulate heart function but fail to tackle the root cause of inflammation. In myocarditis, the initial wave of inflammation is characterized by the presence of neutrophils. Subsequently, neutrophils secrete chemokines and cytokines at the site of heart tissue damage to recruit additional immune cells and regulate defense responses, thereby exacerbating myocarditis. Recent discoveries showing neutrophil extracellular traps (NETs) and their components not only reinforce the proinflammatory functions of neutrophils, inducing enhanced interleukin (IL)-8 secretion, but also induce monocyte/macrophage activation, differentiation, and phagocytic function through the inflammasome pathway. The inflammasome cascade triggers a positive feedback loop through the secretion of proinflammatory cytokines, which leads to further neutrophil activation and degranulation, NET release, monocyte and macrophage infiltration, tissue degradation, and myocardial damage, indicating that neutrophils promote myocarditis-induced cardiac necrosis and an anti-cardiac immune response. In addition, neutrophils can induce oxidative stress and damage cellular structures by releasing excess reactive oxygen species (ROS), thus exacerbating tissue damage in myocarditis. Meanwhile, the recruitment of cells, which is facilitated by neutrophil-secreted chemokines, and the consumption of cells through neutrophil phagocytosis can form a closed loop that continuously maintains a proinflammatory state. This review summarizes the role of neutrophil secretion, phagocytosis and their relationship in myocarditis, and discusses the function of certain agents, such as chemokine antagonists, midkine blockers and neutrophil peptidyl arginine deiminase 4 (PAD4) inhibitors in inhibiting neutrophil secretion and phagocytosis, to provide perspective for myocarditis treatments through the inhibition of neutrophil secretion and phagocytosis.