Tan Zhang

Exercise is a well-established non-pharmacological intervention with wide-ranging benefits for human health. Among its many physiological effects, exercise exerts significant immunomodulatory functions, particularly influencing monocyte and macrophage activity. In this review, we summarize current findings on how acute and chronic exercise of varying modalities affect monocyte/macrophage mobilization, polarization, and function. We also discuss the implications of these changes in the context of exercise-mediated protection against inflammatory, metabolic, oncologic, neurodegenerative, and musculoskeletal diseases. Furthermore, we highlight emerging mechanisms through which exercise modulates monocyte/macrophage biology, including the roles of exerkines, neuroendocrine signaling, and peroxisome proliferator-activated receptors (PPARs). A better understanding of these pathways may offer new insights into the development of exercise-based strategies for immune regulation and disease intervention.

Exercise has been proved to be effective in ameliorating diabetes but the underlying mechanisms remain obscure. It has been recently demonstrated that overactivation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome led to hepatic insulin resistance. Therefore, we aimed to explore the role and underlying mechanism of NLRP3 inflammasome in exercise-mediated hepatic insulin resistance. Wild type and db/db mice were sedentary or subjected to 8-week moderate intensity exercise, liver tissues and primary hepatic macrophages were isolated. Exercise mitigated hepatic steatosis and enhanced the hepatic insulin sensitivity of db/db mice. More importantly, exercise reduced the protein expression of two-pore domain weak inwardly rectifying K⁺ channel 2 (TWIK2) to suppress cellular K⁺ efflux, blunted the generation of mitochondrial ROS (mROS) and the release of oxidized mitochondrial DNA (ox-mtDNA) into cytosol, leading to the inhibition of NLRP3 inflammasome in hepatic macrophages of db/db mice. Accordingly, the hepatic macrophages switched from pro-inflammatory phenotype to anti-inflammatory phenotype and the infiltration of macrophages into liver was decreased in response to exercise. Moreover, inhibition of TWIK2 expression with TWIK2 inhibitor or shRNA interference in hepatic macrophages blunted the TWIK2-mtDNA-NLRP3 inflammasome signaling. The macrophages switched to anti-inflammatory phenotype upon TWIK2 deficiency. Additionally, the insulin sensitivity was elevated in primary hepatocytes which were exposed to culture medium from hepatic macrophages with TWIK2 deficiency, suggesting that inhibition of TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages could attenuate hepatic insulin resistance Taken together, we first observed the inhibition of TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages of diabetic mice in response to exercise intervention, implying a probable role for TWIK2-mtDNA-NLRP3 inflammasome signaling in exercise-mediated alleviation of hepatic inflammation and insulin resistance, hoping to provide theoretical basis and new target for the prevention and treatment of metabolic diseases.

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.

Type 2 diabetes mellitus (T2DM) is one of most common metabolic diseases and continues to be a leading cause of death worldwide. Although great efforts have been made to elucidate the pathogenesis of diabetes, the underlying mechanism still remains unclear. Notably, overwhelming evidence has demonstrated that mitochondria are tightly correlated with the development of T2DM, and the defects of mitochondrial function in peripheral insulin-responsive tissues, such as skeletal muscle, liver and adipose tissue, are crucial drivers of T2DM. Furthermore, exercise training is considered as an effective stimulus for improving insulin sensitivity and hence is regarded as the best strategy to prevent and treat T2DM. Although the precise mechanisms by which exercise alleviates T2DM are not fully understood, mitochondria may be critical for the beneficial effects of exercise.

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.

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.