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1.
Immunol Cell Biol ; 101(8): 735-745, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37253434

RESUMO

Coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) is characterized by immune cell infiltration and myocardial damage. High mobility group box 1 (HMGB1) is a highly conserved nuclear DNA-binding protein that participates in DNA replication, transcriptional regulation, repair response and inflammatory response in different disease models. To investigate the exact function of HMGB1 in CVB3-induced VMC, we crossed Hmgb1-floxed (Hmgb1f/f ) mice with mice carrying a suitable Cre recombinase transgenic strain to achieve conditional inactivation of the Hmgb1 gene in a cardiomyocyte-specific manner and to establish myocarditis. In this study, we found that cardiomyocyte-specific Hmgb1-deficient (Hmgb1f/f TgCre/+ ) mice exhibited exacerbated myocardial injury. Hmgb1-deficient cardiomyocytes may promote early apoptosis via the p53-mediated Bax mitochondrial pathway, as evidenced by the higher localization of p53 protein in the cytosol of Hmgb1-deficient cardiomyocytes upon CVB3 infection. Moreover, cardiomyocyte Hmgb1-deficient mice are more susceptible to cardiac dysfunction after infection. This study provides new insights into HMGB1 in VMC pathogenesis and a strategy for appropriate blocking of HMGB1 in the clinical treatment of VMC.


Assuntos
Infecções por Coxsackievirus , Enterovirus Humano B , Proteína HMGB1 , Miocardite , Animais , Camundongos , Apoptose/genética , Proteína HMGB1/metabolismo , Camundongos Endogâmicos BALB C , Miocardite/imunologia , Miocardite/patologia , Miocardite/virologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína Supressora de Tumor p53/metabolismo , Infecções por Coxsackievirus/imunologia
2.
J Immunol ; 205(11): 3167-3178, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127822

RESUMO

Deubiquitinating enzymes (DUBs) are cysteine proteases that reverse the ubiquitination by removing ubiquitins from the target protein. The human genome encodes ∼100 potential DUBs, which can be classified into six families, influencing multiple cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. To systematically explore the role of DUBs involved in antiviral immunity, we performed an RNA interference-based screening that contains 97 human DUBs. We identified that ubiquitin-specific protease (USP) 39 expression modulates the antiviral activity, which is, to our knowledge, a previously unknown function of this enzyme. Small interfering RNA knockdown of USP39 significantly enhanced viral replication, whereas overexpression of USP39 had an opposite effect. Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK/STAT downstream of type I signaling by enhancing IFN-stimulated response elements promoter activity and expression of IFN-stimulated genes. Interestingly, USP39, previously considered not to have the deubiquitinase activity, in this study is proved to interact with STAT1 and sustain its protein level by deubiqutination. Furthermore, we found that through novel mechanism USP39 can significantly decrease K6-linked but not K48-linked ubiquitination of STAT1 for degradation. Taken together, these findings uncover that USP39 is, to our knowledge, a new deubiquitinase that positively regulates IFN-induced antiviral efficacy.


Assuntos
Antivirais/metabolismo , Interferon Tipo I/metabolismo , Fator de Transcrição STAT1/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular , Feminino , Células HEK293 , Humanos , Camundongos , Interferência de RNA/fisiologia , Transdução de Sinais/fisiologia , Ubiquitinação/fisiologia , Ubiquitinas/metabolismo
3.
Microbes Infect ; 22(1): 46-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31319178

RESUMO

Calpains are calcium-activated neutral cysteine proteases. The dysregulation of calpain activity has been found to be related to cardiovascular diseases, for which calpain inhibition is used as a treatment. Viral myocarditis (VMC) is primarily caused by Coxsackievirus group B3 virus infection (CVB3). CVB3 virus infection induces autophagy and hijacks this process to facilitate its replication. In this study, we found that calpain was significantly activated in hearts affected by VMC. However, pharmacologically inhibiting calpain aggravated VMC symptoms in mice due to myocardial inflammation and cardiac dysfunction. The inhibition of calpain activity in vitro led to the accumulation of LC3-II and increased levels of p62/SQSTM1 protein expression, suggesting that autophagic flux was impaired by calpain inhibition. These effects of calpain inhibition were also observed in capn4-specific myocardial knockout mice in vivo. Furthermore, our results provided evidence that calpain inhibition in VMC, unlike other cardiovascular diseases, exacerbated the disease symptom by impairing CVB3-induced autophagic flux, which may subsequently reduce virus autolysosome degradation. Our findings indicated that calpain inhibition may not be a good treatment for VMC disease in a clinical setting.


Assuntos
Autofagia , Calpaína/metabolismo , Infecções por Coxsackievirus/virologia , Enterovirus Humano B/fisiologia , Miocardite/virologia , Animais , Autofagossomos/metabolismo , Calpaína/antagonistas & inibidores , Calpaína/deficiência , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Replicação Viral
4.
Mol Immunol ; 114: 41-48, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31336248

RESUMO

Viral myocarditis, mainly caused by enteroviruses specially coxsackievirus B3 (CVB3) infection, is a common clinical cardiovascular disease and characterized by cardiac massive inflammation. Our previous study showed that CVB3-induced myocardial NLRP3 contributed to the development of viral myocarditis. In this study, we found that beside of being up-regulated in myocardiocytes, NLPR3 was also obviously increased in the cardiac infiltrating macrophages. While whether this accumulated NLRP3 influences, macrophage inflammatory responses remains unknown. By adoptive transfer assays, we found that mice receiving NLRP3 up-regulated macrophages showed much more abundant cardiac IL-1ß production and more severe myocardial inflammation, while those receiving NLRP3 down-regulated macrophages showed much less IL-1ß production and milder myocarditis, indicating that NLRP3 up-regulated macrophages played a pathological role in CVB3-induced myocarditis. In addition, we further found that it was CVB3 capsid proteins VP1 (predominant) and VP2, but not viral RNAs, robustly triggered macrophage NLRP3 up-regulation and activation. Our study demonstrated macrophage NLRP3 inflammasome could be efficiently be activated by CVB3 capsid proteins, and contributed to the pathogenesis of viral myocarditis. It might provide some clues to the development of new therapeutic strategies based on macrophage NLRP3 modulation.


Assuntos
Proteínas do Capsídeo/imunologia , Infecções por Coxsackievirus/imunologia , Enterovirus/imunologia , Inflamassomos/imunologia , Macrófagos/imunologia , Miocardite/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Transferência Adotiva/métodos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/imunologia , Células HeLa , Coração/virologia , Humanos , Inflamação/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/virologia , Miocárdio/imunologia , Células RAW 264.7 , Regulação para Cima/imunologia , Viroses/imunologia , Viroses/virologia
5.
Int Immunopharmacol ; 70: 504-511, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30884430

RESUMO

Streptococcus aureus (S. aureus)-induced acute lung injury (ALI) has a high incidence of mortality clinically. Glycyrrhizin (GL) is a traditional Chinese medicine for anti-inflammatory. However, the role of GL in S. aureus-induced ALI has not previously been elucidated. GL (25 mg/kg i.p.) administration exerts potent anti-inflammatory effect in this model. GL administration significantly alleviated inflammation via reduction of multiple cytokines (serum and lung tissue IL-6, TNF-α, IL-8, IL-1ß and HMGB1) and immune cells (lung tissue neutrophil and macrophage infiltration). Additionally, we measured the signaling pathways (NF-kB and MARKs) and inflammasome dependent pyroptosis. The results suggest that GL inhibits NF-kB, p38/ERK pathways and pyroptosis. Furthermore, we used different inhibitors to treat infected-A549 cells and found that BMS-582949 (a p38 inhibitor) is the most effective inhibitor for inhibiting pro-inflammatory cytokines (IL-6, TNF-α and IL-1ß) production, which suggests that p38 signaling pathway might be the main pathway for S. aureus-induced inflammation. Collectively, the data demonstrates that GL could mitigate inflammation after S. aureus infection.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Ácido Glicirrízico/uso terapêutico , Macrófagos/imunologia , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus/fisiologia , Células A549 , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Transdução de Sinais
6.
Sci Rep ; 7: 42162, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28176833

RESUMO

Infiltrating macrophages have been proven as a pivotal pathological inflammatory cell subset in coxsackievirus B3 (CVB3) induced viral myocarditis. However, the mechanisms underlying the initiation and promotion of macrophage pro-inflammatory responses are still blur. We previously reported that cardiac ER stress contributed to CVB3-induced myocarditis by augmenting inflammation. In this study, we focused on the influence of ER stress on the macrophage inflammatory responses in the viral myocarditis. We found that ER stress was robustly induced in the cardiac infiltrating macrophages from CVB3-infected mice, and robustly facilitated the production of pro-inflammatory cytokines (IL-6, IL-12, MCP-1 and IP-10). Consistently, adoptive transfer of ER stressed macrophages significantly worsened the viral myocarditis; while transfer of ER stress-inhibited macrophages obviously alleviated the myocarditis. To our surprise, this significantly activated ER stress was not directly caused by the virus stimulation, but was transferred from the CVB3-infected, ER stressed myocardiocytes via soluble molecules in a TLR2, 4-independent way. In the present study, we reported that the transmissible ER stress from the infected myocardiocytes to macrophages could augment the pro-inflammatory responses and promoted the pathogenesis of viral myocarditis. Blocking ER stress transmission, instead of inhibiting its initiation, may represent novel therapeutic strategies against viral myocarditis.


Assuntos
Estresse do Retículo Endoplasmático , Infecções por Enterovirus/patologia , Macrófagos/virologia , Miocardite/patologia , Miócitos Cardíacos/virologia , Transferência Adotiva , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Enterovirus Humano B/patogenicidade , Enterovirus Humano B/fisiologia , Infecções por Enterovirus/genética , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Expressão Gênica , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/patologia , Macrófagos/transplante , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/genética , Miocardite/imunologia , Miocardite/virologia , Miócitos Cardíacos/patologia
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