NLRP3 is an important pattern recognition receptor in the innate immune system, and its activation induces a large number of pro-inflammatory cytokines, IL-1β and IL-18 which are involved in the development of various diseases. In recent years, it has been suggested that mitochondria are the platform for NLRP3 inflammasome activation. Additionally, exercise is considered as an important intervention strategy to mediate the innate immune responses. Generally, chronic moderate-intensity endurance training, resistance training and high-intensity interval training inhibit NLRP3 inflammasome activation in response to various pathological factors. In contrast, acute exercise activates NLRP3 inflammasome. However, the mechanisms by which exercise regulates NLRP3 inflammasome activation are largely unclear. Therefore, the mechanism of NLRP3 inflammasome activation is discussed mainly from the perspective of mitochondria in this review. Moreover, the effect and potential mechanism of exercise on NLRP3 inflammasome are explored, hoping to provide new target for relevant research.

Background: Diabetes is one of the most common metabolic diseases and continues to be a leading cause of death worldwide. The NLRP3 inflammasome has been shown to exert detrimental effects on diabetic models. However, evidence linking NLRP3 inflammasome and pre-diabetes has been scarcely explored. Herein, we aimed to determine whether the NLRP3 inflammasome correlates with insulin resistance and liver pathology in a cohort of pre-diabetic subjects.Methods: 50 pre-diabetic subjects were randomly assigned to a Pre-diabetes Control (DC, n=25) and a Pre-diabetes exercise (DEx, n=25) group. 25 Normal subjects (NC) were selected as controls. The DEx group performed a 6-month combined Yijingjing and resistance training intervention, while DC and NC group remained daily routines. Clinical metabolic parameters were determined with an automatic biochemistry analyzer; inflammatory cytokines were quantified by the ELISA assay; the protein expressions of NLRP3 inflammasome components in PBMCs were evaluated by Western Blot.Results: The insulin resistance, liver injury and NLRP3 inflammasome activity were higher in pre-diabetic individuals than in normal control group. However, 6-month exercise intervention counteracted this trend, significantly improved insulin sensitivity, reduced liver injury and inhibited the overactivation of NLRP3 inflammasome in pre-diabetic subjects. Moreover, positive correlations between insulin resistance, liver pathology and NLRP3 inflammasome were also found.Conclusions: Our study suggests that exercise training is an effective strategy to alleviate insulin resistance and liver injury in elderly pre-diabetic subjects which is probably associated with the inhibition of NLRP3 inflammasome activity.

Mitochondria are considered as “the plant of power” with cells for a long time. However, recent researches suggest that mitochondria also take part in innate immune response to a great extent. Remarkably, mtDNA was reported to have immunnostimulatory potential in 2004. Since then, there has been rapid growth in understanding the role of mtDNA in innate immune. The mtDNA is released into cytosol, extracellular environment, or circulating blood through BAK/BAX pore, mPTP, and GSDMD pore upon mitochondrial damage, where it is recognized by PRRs including TLR9, cGAS, and NLRP3, thereby triggering innate immune response. On the other hand, regular exercise has been recognized as an effective intervention strategy for innate immune response. Some studies show that chronic moderate-intensity endurance exercise, resistance training, HIIT, and moderate-intensity acute exercise enhance mitochondrial function by promoting mtDNA transcription and replication, thus blunting the abnormal release of mtDNA and excessive innate immune response. On the contrary, high-intensity acute exercise elicits the opposite effect. Nevertheless, only a very small body of research by far has been performed to illustrate the impact of exercise on mtDNA-driven innate immune response, and an overall review is lacking. In light of these, we summarize the current knowledge on the mechanism mediating the release of mtDNA, the role of mtDNA in innate immune response and the influence of exercise on mtDNA leakage, hoping to pave the way to investigate new diagnostic and therapeutic approaches for immunopathies.