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1.
Cell ; 186(14): 3013-3032.e22, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-37352855

RESUMO

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.


Assuntos
Cardiotoxicidade , DNA Mitocondrial , Animais , Camundongos , DNA Mitocondrial/metabolismo , Imunidade Inata , Interferons/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Fosforilação
2.
Sci Adv ; 7(22)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34039599

RESUMO

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune cross-talk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces health span, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (NRF2), which increases oxidative stress, enhances proinflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related disorders and aging.


Assuntos
DNA Mitocondrial , Interferon Tipo I , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Inflamação/genética , Inflamação/metabolismo , Interferon Tipo I/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
3.
Curr Opin Immunol ; 25(1): 103-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23246037

RESUMO

Gamma-interferon-inducible lysosomal thiol reductase (GILT), a thioredoxin-related oxidoreductase, functions in MHC class II-restricted antigen processing and MHC class I-restricted cross-presentation by reducing disulfide bonds of endocytosed proteins and facilitating their unfolding and optimal degradation. However, recent reports have greatly expanded our understanding of GILT's function. Several studies of GILT and antigen processing have shown that the influence of GILT on the peptide repertoire can alter the character of the immune response and affect central tolerance. Furthermore, a few unexpected roles for GILT have been uncovered: as a host factor for Listeria monocytogenes infection, in the maintenance of cellular glutathione (GSH) levels, and possibly outside the cell, as enzymatically active GILT is secreted by activated macrophages.


Assuntos
Autoantígenos/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Macrófagos/imunologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/imunologia , Animais , Apresentação de Antígeno , Autoantígenos/imunologia , Glutationa/metabolismo , Humanos , Tolerância Imunológica , Imunidade Celular , Listeria monocytogenes/patogenicidade , Oxirredução
4.
PLoS One ; 8(1): e51343, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23326313

RESUMO

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is known to reduce disulfide bonds present in proteins internalized by antigen presenting cells, facilitating optimal processing and presentation of peptides on Major Histocompatibility Complex class II molecules, as well as the subsequent activation of CD4-positive T lymphocytes. Here, we show that GILT is required for class II-restricted processing and presentation of immunodominant epitopes from the major house dust mite allergen Der p 1. In the absence of GILT, CD4-positive T cell responses to Der p 1 are significantly reduced, resulting in mitigated allergic airway inflammation in response to Der p 1 and house dust mite extracts in a murine model of asthma.


Assuntos
Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Cisteína Endopeptidases/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Oxirredutases/imunologia , Animais , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Ácido Aspártico Endopeptidases/imunologia , Asma/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Células Cultivadas , Baratas/imunologia , Técnicas de Cocultura , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredutases/genética , Oxirredutases/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Pyroglyphidae/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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