Original Article: https://doi.org/10.1016/j.cell.2020.08.031
- Cardiomyocytes are the cells responsible for generating contractile force in the intact heart.
- Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart.
- Cardiomyocytes are long-lived and rarely renewed.
- It is unclear whether these cardiomyocytes manage to preserve homeostasis on their own.
- Researchers discovered that macrophages lodged within the health heart tissue, actively took material, including mitochondria, derived from cardiomyocytes.
- Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers.
- The ejection process is driven by the cardiomyocyte’s autophagy machinery that was enhanced during cardiac stress.
- Autophagy is the natural, regulated mechanism of the cell that removes unnecessary or dysfunctional cellular components.
- Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction.
- Inflammasome refers to the multiprotein intracellular complex that detects pathogens and sterile stressors, and that activates the highly pro-inflammatory cytokines.
- The conclusion identify an immune-tissue pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function.
Klionsky DJ (August 2008). “Autophagy revisited: a conversation with Christian de Duve”. Autophagy. 4 (6): 740–3. doi:10.4161/auto.6398. PMID 18567941.
Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte’s autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function.
Keywords: autophagy; heart; macrophage; mitochondria; phagocytosis; proteostasis.
The immune system is essential for the development and homeostasis of the human body. Our current understanding of the immune system on disease pathogenesis has drastically expanded over the last decade with the definition of additional non-canonical roles in various tissues. Recently, tissue-resident immune cells have become an important research topic for understanding their roles in the prevention, pathogenesis, and recovery from the diseases. Heart resident immune cells, particularly macrophage subtypes, and their characteristic morphology, distribution in the cardiac tissue, and transcriptional profile have been recently reported in the experimental animal models, unrevealing novel and unexpected roles in electrophysiological regulation of the heart both at the steady-state and diseased state. Immunological processes have been widely studied in both sterile cardiac disorders, such as myocardial infarction, autoimmune cardiac diseases, or infectious cardiac diseases, such as myocarditis, endocarditis, and acute rheumatic carditis. Following cardiac injury, innate and adaptive immunity have critical roles in pro- and anti-inflammatory processes. Heart resident immune cells not only provide defense against infectious diseases but also contribute to the homeostasis. In recent years, physiological changes and pathological processes were demonstrated to alter the abundance, distribution, polarization, and diversity of immune cells in the heart. Accumulating evidence indicates that cardiac remodeling is controlled by the complex crosstalk between cardiomyocytes and cardiac immune cells through the gap junctions, providing the ion flow to achieve synchronization and modulation of contractility. This review article aims to review the well-documented roles of both resident and recruited immune cell in the heart, as well as their recently uncovered unconventional roles in both cardiac homeostasis and cardiovascular diseases. We have mostly focused on studies on animal models used in preclinical research, underlying the need for further investigations in humans or in vitro human models. It may be foreseen that the further comprehensive investigations of cardiac immunology might harbor new therapeutic options for cardiac disorders that have tremendous medical potential.
Keywords: Cardiac diseases; Cardiology; Cardiomyocytes; Immunoelectrophysiology; Immunology.
Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrix-degrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.
Keywords: Chemokine; Cytokine; Heart failure; Inflammation; Interleukin-1; TNF-α.