Autoimmune diseases are a group of heterogeneous diseases with diverse clinical manifestations that can be divided into systemic and organ-specific. The common etiology of autoimmune diseases is the destruction of immune tolerance and the production of autoantibodies, which attack specific tissues and/or organs in the body. The pathogenesis of autoimmune diseases is complicated, and genetic, environmental, infectious, and even psychological factors work together to cause aberrant innate and adaptive immune responses. Although the exact mechanisms are unclear, recently, excessive exacerbation of pyroptosis, as a bond between innate and adaptive immunity, has been proven to play a crucial role in the development of autoimmune disease. Pyroptosis is characterized by pore formation on cell membranes, as well as cell rupture and the excretion of intracellular contents and pro-inflammatory cytokines, such as IL-1β and IL-18. This overactive inflammatory programmed cell death disrupts immune system homeostasis and promotes autoimmunity. This review examines the molecular structure of classical inflammasomes, including NLRP3, AIM2, and P2X7-NLRP3, as the switches of pyroptosis, and their molecular regulation mechanisms. The sophisticated pyroptosis pathways, including the canonical caspase-1-mediated pathway, the noncanonical caspase-4/5/11-mediated pathway, the emerging caspase-3-mediated pathway, and the caspase-independent pathway, are also described. We highlight the recent advances in pyroptosis in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjögren’s syndrome and dermatomyositis, and attempt to identify its potential advantages as a therapeutic target or prognostic marker in these diseases.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.841732/pdf

Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy.

Pyroptosis is a kind of programmed cell death closely related to inflammation. The pathways that mediate pyroptosis can be divided into the Caspase-1-dependent canonical pathway and the Caspase4/5/11-dependent non-canonical pathway. The most significant difference from other cell death is that pyroptosis rapidly causes rupture of the plasma membrane, cell expansion, dissolution and rupture of the cell membrane, the release of cell contents and a large number of inflammatory factors, and send pro-inflammatory signals to adjacent cells, recruit inflammatory cells and induce inflammatory responses. Cardiac remodeling is the basic mechanism of heart failure (HF) and the core of pathophysiological research on the underlying mechanism. A large number of studies have shown that pyroptosis can cause cardiac fibrosis, cardiac hypertrophy, cardiomyocytes death, myocardial dysfunction, excessive inflammation, and cardiac remodeling. Therefore, targeting pyroptosis has a good prospect in improving cardiac remodeling in HF. In this review, the basic molecular mechanism of pyroptosis is summarized, the relationship between pyroptosis and cardiac remodeling in HF is analyzed in-depth, and the potential therapy of targeting pyroptosis to improve adverse cardiac remodeling in HF is discussed, providing some ideas for improving the study of adverse cardiac remodeling in HF.

Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

Abstract Since the discovery of cell apoptosis, other gene-regulated cell deaths are gradually appreciated, including pyroptosis, ferroptosis, and necroptosis. Necroptosis is, so far, one of the best-characterized regulated necrosis. In response to diverse stimuli (death receptor or toll-like receptor stimulation, pathogenic infection, or other factors), necroptosis is initiated and precisely regulated by the receptor-interacting protein kinase 3 (RIPK3) with the involvement of its partners (RIPK1, TRIF, DAI, or others), ultimately leading to the activation of its downstream substrate, mixed lineage kinase domain-like (MLKL). Necroptosis plays a significant role in the host’s defense against pathogenic infections. Although much has been recognized regarding modulatory mechanisms of necroptosis during pathogenic infection, the exact role of necroptosis at different stages of infectious diseases is still being unveiled, e.g., how and when pathogens utilize or evade necroptosis to facilitate their invasion and how hosts manipulate necroptosis to counteract these detrimental effects brought by pathogenic infections and further eliminate the encroaching pathogens. In this review, we summarize and discuss the recent progress in the role of necroptosis during a series of viral, bacterial, and parasitic infections with zoonotic potentials, aiming to provide references and directions for the prevention and control of infectious diseases of both human and animals. 

/pdf/regulated-necrosis-a-proinflammatory-cell-death-potentially-2y2uj3jm.pdf

Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections

Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.

Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.

Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.

/pdf/trimetazidine-attenuates-dexamethasone-induced-muscle-a7ozgvo34u.pdf

Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis.

BACKGROUND Unintentional weight loss (cachexia) has been associated with poor outcomes in chronic heart failure (CHF). Meteorin-like (Metrnl) is a novel myokine with protective effects on cardiovascular diseases. However, the change of Metrnl concentrations and its role in elderly patients with CHF remains unclear. The aim of this study was to evaluate the association of serum Metrnl with weight loss and outcomes in elderly patients with CHF. METHODS A total of 931 consecutive elderly patients (aged 60 years and older) with CHF and 135 age-matched and sex-matched control subjects were enrolled. Serum Metrnl concentration was measured by enzyme-linked immunosorbent assay. Body weight was measured at baseline and 12 months. RESULTS Median of serum Metrnl levels was lower in CHF patients when compared with controls [201.31 (184.95-261.16) pg/mL vs. 168.68 (103.15-197.54) pg/mL, P  5% weight loss from baseline to 12 months [odds ratio = 6.13, 95% confidence interval (CI) = 2.57-14.62 per log decrease; P < 0.001]. Serum Metrnl levels were decreased as LVEF decreased (P < 0.001) and were positively correlated with LVEF (r = 0.267, P < 0.001) but negatively correlated with NT-proBNP levels (r = -0.257, P < 0.001). Cox regression analysis suggested that lower serum Metrnl was associated with higher cardiovascular mortality [hazard ratio (HR) = 6.71, 95% CI = 3.41-13.18 per log decrease; P < 0.001], CHF rehospitalization (HR = 3.07, 95% CI = 1.82-5.17 per log decrease; P < 0.001), and the combined major adverse cardiac event(s) (MACEs) (HR = 5.38, 95% CI = 3.51-8.25 per log decrease; P < 0.001). The Kaplan-Meier survival curves showed that low concentration of Metrnl was a prognostic indicator of MACEs in patients with CHF. CONCLUSIONS Our study suggests that lower serum Metrnl level is correlated with weight loss and the severity of cardiac dysfunction in elderly patients with CHF.

Serum Meteorin-like is associated with weight loss in the elderly patients with chronic heart failure.

Background Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular morbidity and mortality worldwide. Pyroptosis is a form of inflammatory cell death that plays a major role in the development and progression of cardiac injury in AMI. However, the underlying mechanisms for the activation of pyroptosis during AMI are not fully elucidated. Methods and Results Here we show that RBP4 (retinol-binding protein 4), a previous identified proinflammatory adipokine, was increased both in the myocardium of left anterior descending artery ligation-induced AMI mouse model and in ischemia-hypoxia‒induced cardiomyocyte injury model. The upregulated RBP4 may contribute to the activation of cardiomyocyte pyroptosis in AMI because overexpression of RBP4 activated NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome, promoted the precursor cleavage of Caspase-1, and subsequently induced GSDMD (gasdermin-D)-dependent pyroptosis. In contrast, knockdown of RBP4 alleviated ischemia-hypoxia‒induced activation of NLRP3 inflammasome signaling and pyroptosis in cardiomyocytes. Mechanistically, coimmunoprecipitation assay showed that RBP4 interacted directly with NLRP3 in cardiomyocyte, while genetic knockdown or pharmacological inhibition of NLRP3 attenuated RBP4-induced pyroptosis in cardiomyocytes. Finally, knockdown of RBP4 in heart decreased infarct size and protected against AMI-induced pyroptosis and cardiac dysfunction in mice. Conclusions Taken together, these findings reveal RBP4 as a novel modulator promoting cardiomyocyte pyroptosis via interaction with NLRP3 in AMI. Therefore, targeting cardiac RBP4 might represent a viable strategy for the prevention of cardiac injury in patients with AMI.

Retinol-Binding Protein 4 Promotes Cardiac Injury After Myocardial Infarction Via Inducing Cardiomyocyte Pyroptosis Through an Interaction With NLRP3.

/pdf/trimetazidine-attenuates-dexamethasone-induced-muscle-544g2tlge4.pdf

Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis

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Papers

Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis.

Serum Meteorin-like is associated with weight loss in the elderly patients with chronic heart failure.

Retinol-Binding Protein 4 Promotes Cardiac Injury After Myocardial Infarction Via Inducing Cardiomyocyte Pyroptosis Through an Interaction With NLRP3.

Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis