Abstract
Dendritic cells (DCs) are vital antigen-presenting cells (APCs) in the immune system, whose apoptosis is closely related to the development of sepsis. Mitophagy is one of the necessary forms of selective autophagy that removes damaged or dysfunctional mitochondria to regulate immunity and inflammation. However, its effect on the apoptosis of DC in sepsis remains unknown. Here, we showed that sepsis activated the apoptosis and mitophagy of DC, and mitophagy had an anti-apoptotic effect on sepsis-induced DC apoptosis. In this study, we used cecal ligation and puncture (CLP) to simulate the pathophysiological state of sepsis. Apoptosis and mitophagy of DC were significantly enhanced in CLP mice compared with controls, and in the Pink1-KO (Pink1-knockout) mice CLP model, the level of apoptosis in DC was further increased while the level of mitophagy was decreased. In addition, more severe mitochondrial dysfunction was exhibited in DC of Pink1-KO mice CLP model compared to wild-type (WT) mice. The results suggest that Pink1/Parkin-mediated mitophagy is activated during sepsis and has an anti-apoptotic effect on DC, which regulates immune functions.
Highlights
Mitophagy, a selective autophagic process, is targeted for eliminating dysfunctional or nonessential mitochondria from the population to maintain cellular homeostasis [1, 2]
Our previous study found that membrane potential (MMP) reduction and mitophagy were induced by the late septic inflammatory factor high mobility group box-1 protein (HMGB1), which is closely related to the expression of the Parkin mitochondrial receptor protein Mfn2, suggesting that mitophagy may be involved in the pathogenesis of sepsis [7, 8]
Sepsis-induced immune cell apoptosis is considered to be a key factor in the immunosuppression of sepsis
Summary
A selective autophagic process, is targeted for eliminating dysfunctional or nonessential mitochondria from the population to maintain cellular homeostasis [1, 2]. Inhibition of mitophagy leads to an increase in the number of mitochondria and ROS content in mature T lymphocytes, resulting in impaired peripheral survival [3, 9]. Another recent report highlights the critical role of mitophagy in the maintenance of innate immune homeostasis [10]. We hypothesized that during sepsis, mitophagy was engaged in the regulation of the apoptosis of DCs by a mechanism that may involve the Pink1-Parkin signaling pathway. We attempted to analyze the mechanism of the Pink1-Parkin signaling pathway in regulating the apoptosis of DCs in sepsis and to further elucidate the essential link between mitophagy and DCs apoptosis. These findings expanded the understanding of Pink1/Parkin-medicated mitophagy regulating apoptosis in immune cells during sepsis, which may represent a novel therapeutic target in sepsis-related apoptosis of DCs
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