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1.
Immunity ; 57(7): 1443-1445, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38986436

RESUMEN

RIPK1 is known as a driver of cell death and inflammation. In this issue of Immunity, Imai et al. and Mannion et al. find that these same processes are also induced by RIPK1 inactivation and highlight the therapeutic potential of RIPK1 elimination.


Asunto(s)
Inflamación , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Inflamación/inmunología , Humanos , Animales , Muerte Celular/inmunología , Ratones
2.
Nature ; 607(7920): 769-775, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35859177

RESUMEN

The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3-5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7-9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.


Asunto(s)
Adenosina Desaminasa , Enfermedades del Sistema Inmune , Inflamación , Mutación , Proteínas de Unión al ARN , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Animales , Caspasa 8/genética , Caspasa 8/metabolismo , Muerte Celular , Eliminación de Gen , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/metabolismo , Enfermedades del Sistema Inmune/patología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Mamíferos/genética , Proteínas Quinasas/deficiencia , Proteínas Quinasas/genética , ARN Bicatenario/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de Señal
3.
J Immunol ; 207(10): 2417-2422, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34663621

RESUMEN

Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor with an essential role in cytoskeletal rearrangement, cell migration, and survival of various immune cells. Interestingly, DOCK8-deficient mice are resistant to the development of experimental autoimmune encephalomyelitis (EAE). To understand if EAE resistance in these mice results from an alteration in dendritic cell (DC) functions, we generated mice with conditional deletion of DOCK8 in DCs and observed attenuated EAE in these mice compared with control mice. Additionally, we demonstrated that DOCK8 is important for the existence of splenic conventional DC2 and lymph node migratory DCs and further established that migratory DC, rather than resident DC, are essential for the generation and proliferation of pathogenic T cell populations upon immunization with myelin Ag in adjuvant. Therefore, our data suggest that limiting migratory DCs through DOCK8 deletion and possibly other mechanisms could limit the development of CNS autoimmunity.


Asunto(s)
Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Factores de Intercambio de Guanina Nucleótido/inmunología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL
4.
Sci Immunol ; 9(91): eabq6541, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38181093

RESUMEN

Pore-forming toxins (PFTs) are the largest class of bacterial toxins and contribute to virulence by triggering host cell death. Vertebrates also express endogenous pore-forming proteins that induce cell death as part of host defense. To mitigate damage and promote survival, cells mobilize membrane repair mechanisms to neutralize and counteract pores, but how these pathways are activated is poorly understood. Here, we use a transposon-based gene activation screen to discover pathways that counteract the cytotoxicity of the archetypal PFT Staphylococcus aureus α-toxin. We identify the endolysosomal protein LITAF as a mediator of cellular resistance to PFT-induced cell death that is active against both bacterial toxins and the endogenous pore, gasdermin D, a terminal effector of pyroptosis. Activation of the ubiquitin ligase NEDD4 by potassium efflux mobilizes LITAF to recruit the endosomal sorting complexes required for transport (ESCRT) machinery to repair damaged membrane. Cells lacking LITAF, or carrying naturally occurring disease-associated mutations of LITAF, are highly susceptible to pore-induced death. Notably, LITAF-mediated repair occurs at endosomal membranes, resulting in expulsion of damaged membranes as exosomes, rather than through direct excision of pores from the surface plasma membrane. These results identify LITAF as a key effector that links sensing of cellular damage to repair.


Asunto(s)
Toxinas Bacterianas , Piroptosis , Animales , Muerte Celular , Membrana Celular , Endosomas
5.
Sci Immunol ; 4(36)2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31227597

RESUMEN

Although the signaling events that induce different forms of programmed cell death are well defined, the subsequent immune responses to dying cells in the context of cancer remain relatively unexplored. Necroptosis occurs downstream of the receptor-interacting protein kinases RIPK1 and RIPK3, whose activation leads to lytic cell death accompanied by de novo production of proinflammatory mediators. Here, we show that ectopic introduction of necroptotic cells to the tumor microenvironment promotes BATF3+ cDC1- and CD8+ leukocyte-dependent antitumor immunity accompanied by increased tumor antigen loading by tumor-associated antigen-presenting cells. Furthermore, we report the development of constitutively active forms of the necroptosis-inducing enzyme RIPK3 and show that delivery of a gene encoding this enzyme to tumor cells using adeno-associated viruses induces tumor cell necroptosis, which synergizes with immune checkpoint blockade to promote durable tumor clearance. These findings support a role for RIPK1/RIPK3 activation as a beneficial proximal target in the initiation of tumor immunity. Considering that successful tumor immunotherapy regimens will require the rational application of multiple treatment modalities, we propose that maximizing the immunogenicity of dying cells within the tumor microenvironment through specific activation of the necroptotic pathway represents a beneficial treatment approach that may warrant further clinical development.


Asunto(s)
Necroptosis/inmunología , Neoplasias/inmunología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Dependovirus/genética , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células 3T3 NIH , Receptor de Muerte Celular Programada 1/inmunología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de Señal , Microambiente Tumoral/inmunología
6.
Blood Adv ; 2(9): 987-999, 2018 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-29720491

RESUMEN

Hematopoietic stem-cell gene therapy is a promising treatment of X-linked severe combined immunodeficiency disease (SCID-X1), but currently, it requires recipient conditioning, extensive cell manipulation, and sophisticated facilities. With these limitations in mind, we explored a simpler therapeutic approach to SCID-X1 treatment by direct IV administration of foamy virus (FV) vectors in the canine model. FV vectors were used because they have a favorable integration site profile and are resistant to serum inactivation. Here, we show improved efficacy of our in vivo gene therapy platform by mobilization with granulocyte colony-stimulating factor (G-CSF) and AMD3100 before injection of an optimized FV vector incorporating the human phosphoglycerate kinase enhancerless promoter. G-CSF/AMD3100 mobilization before FV vector delivery accelerated kinetics of CD3+ lymphocyte recovery, promoted thymopoiesis, and increased immune clonal diversity. Gene-corrected T lymphocytes exhibited a normal CD4:CD8 ratio and a broad T-cell receptor repertoire and showed restored γC-dependent signaling function. Treated animals showed normal primary and secondary antibody responses to bacteriophage immunization and evidence for immunoglobulin class switching. These results demonstrate safety and efficacy of an accessible, portable, and translatable platform with no conditioning regimen for the treatment of SCID-X1 and other genetic diseases.


Asunto(s)
Enfermedades de los Perros , Terapia Genética , Vectores Genéticos/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética , Compuestos Heterocíclicos/farmacología , Spumavirus , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X , Animales , Bencilaminas , Relación CD4-CD8 , Ciclamas , Modelos Animales de Enfermedad , Enfermedades de los Perros/sangre , Enfermedades de los Perros/genética , Enfermedades de los Perros/terapia , Perros , Humanos , Fosfoglicerato Quinasa/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/sangre , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapia , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/veterinaria
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