RESUMO
Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.
Assuntos
Inibidores de Checkpoint Imunológico , Proteínas de Membrana , Miocardite , Nucleotidiltransferases , Piroptose , Animais , Miocardite/imunologia , Miocardite/patologia , Miocardite/induzido quimicamente , Miocardite/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Camundongos , Masculino , Humanos , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Transdução de Sinais , Camundongos Endogâmicos C57BL , Camundongos Knockout , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Feminino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , GasderminasRESUMO
BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.
RESUMO
Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Gasderminas , Piroptose , Animais , Humanos , Masculino , Camundongos , Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Falência Hepática/metabolismo , Falência Hepática/induzido quimicamente , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piroptose/efeitos dos fármacosRESUMO
Significance: Pyroptosis is a discovered programmed cell death that is mainly executed by the gasdermin protein family. Cell swelling and membrane perforation are observed when pyroptosis occurs, and is accompanied by the liberation of cell contents. Recent Advances: As the study of pyroptosis continues to progress, there is increasing evidence that pyroptosis influences the development of tumors. In addition, the relationship between pyroptosis and tumor is diverse for different tissues and cells. Critical Issues: In this review, we first introduce the research history and molecular mechanisms of pyroptosis. Then we specifically discuss the link between pyroptosis and metabolic and oxidation in tumorigenesis. In the subsequent sections, we focus on the induction of pyroptosis in cancer and its potential role as a promising target for cancer therapy, and discuss the implications of pyroptosis in tumor treatment. In addition, we further summarize the therapeutic value of pyroptosis in tumor treatment. Future Directions: A detailed understanding of the role played by pyroptosis in tumors will help us to further explore tumor formation and progression and provide ideas for the development of new pyroptosis-based therapeutic approaches for patients. Antioxid. Redox Signal. 39, 512-530.
Assuntos
Neoplasias , Piroptose , Humanos , Piroptose/fisiologia , Apoptose/fisiologia , Neoplasias/metabolismo , Carcinogênese , Transformação Celular Neoplásica , OxirreduçãoRESUMO
AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.
Assuntos
Vesículas Extracelulares , Sirtuínas , Humanos , Camundongos , Animais , Idoso , Pré-Escolar , Fibronectinas/metabolismo , Fatores de Transcrição/metabolismo , Camundongos Knockout , Envelhecimento , Angiotensina II/farmacologia , Inflamação/metabolismo , Músculo Esquelético/metabolismo , Proteínas de Choque Térmico HSP40/metabolismoRESUMO
OBJECTIVE: The purpose was to explore the clinical effects and safety of gemcitabine plus nedaplatin in the treatment of advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: From March 2014 to August 2015, we recruited 63 advanced nasopharyngeal carcinoma patients in our hospital. Moreover, the 62 cases were randomly divided into control group (n = 31) and treatment group (n = 32). Patients in the control groups were treated with 5-fluorouracil 500 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1-5 plus cisplatin 20 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1-5 with 21 days per cycle for 3 cycles; Moreover, patients in the treatment group were given gemcitabine 1000 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1 and 8 plus nedaplatin 20 mg/m 2 + 500 ml 0.9% sodium chloride injection intervenous drop infusion in day 1 with 21 days per cycle for 3 cycles. The objective response rate (ORR) and chemotherapy-associated toxicities were compared between the two groups. RESULTS: After 3 cycle chemotherapy, the ORR was 41.9% and 78.1% in the control and treatment group, respectively, with statistical difference (P < 0.05); The main chemotherapy-related toxicity were hematological toxicity and gastrointestinal reaction with no statistical difference between the two groups (P > 0.05). CONCLUSION: The ORR was relative high for gemcitabine plus nedaplatin in the treatment of advanced nasopharyngeal carcinoma with main toxicity of hematological toxicity and gastrointestinal reaction.