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1.
Lupus Sci Med ; 10(1)2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36822800

RESUMO

OBJECTIVE: The aim of the study was to investigate whether the IRAK1/JAK2/Flt3 inhibitor pacritinib prevents disease development in the lupus-prone ABIN1[D485N] knock-in mouse. METHODS: ABIN1[D485N] knock-in mice aged 8 weeks were fed for 10 weeks on a diet containing pacritinib. Body weight was monitored, and serum collected at the end to measure pacritinib, autoantibody and immunoglobulin levels. Splenic immune cell populations were analysed, and the kidney, liver and lungs examined for pathology. RESULTS: Pacritinib prevented multiple facets of the lupus phenotype in ABIN1[D485N] knock-in mice, including splenomegaly, expansion of splenic germinal centre B cells, follicular T helper cells, and neutrophils, elevated serum levels of double-stranded DNA antibodies and immunoglobulins, glomerular IgA and lung inflammation. CONCLUSIONS: Pacritinib may be useful for the treatment of multiorgan inflammation in patients with lupus.


Assuntos
Lúpus Eritematoso Sistêmico , Animais , Camundongos , Inflamação , Rim/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Fenótipo
2.
EMBO Rep ; 22(10): e50743, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34403206

RESUMO

The rapid formation and activation of the NLRP3 inflammasome is induced by co-stimulation with LPS and nigericin. It requires the LPS-stimulated activation of IKKß, which exerts its effects independently of de novo gene transcription, protein translation and other protein kinases activated by IKKß. IKKß is not required for the nigericin-induced dispersion of the trans-Golgi network (TGN), but to bring NLRP3 in proximity with TGN38. The nigericin-induced dispersion of the Golgi is enhanced by co-stimulation with LPS, and this enhancement is IKKß-dependent. Prolonged stimulation with LPS to increase the expression of NLRP3, followed by stimulation with nigericin, produced larger TGN38-positive puncta, and the ensuing activation of the NLRP3 inflammasome was also suppressed by IKKß inhibitors added prior to stimulation with nigericin. IKKß therefore has a key role in recruiting NLRP3 to the dispersed TGN, leading to the formation and activation of the NLRP3 inflammasome.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Quinase I-kappa B , Inflamassomos/genética , Interleucina-1beta , Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nigericina , Rede trans-Golgi
3.
FEBS J ; 288(20): 5909-5924, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33932090

RESUMO

The atypical E3 ligase HOIL-1 forms ester bonds between ubiquitin and serine/threonine residues in proteins, but the physiological roles of this unusual modification are unknown. We now report that IL-18 signalling leading to the production of interferon γ (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is enhanced in cytotoxic T cells from knock-in mice expressing the E3 ligase-inactive HOIL-1[C458S] mutant, demonstrating that the formation of HOIL-1-catalysed ester-linked ubiquitin bonds restricts the activation of this pathway. We show that the interaction of IRAK2 with TRAF6 is required for IL-18-stimulated IFN-γ and GM-CSF production, and that the increased production of these cytokines in cytotoxic T cells from HOIL-1[C458S] mice correlates with an increase in both the number and size of the Lys63/Met1-linked hybrid ubiquitin chains attached to IRAK2 in these cells. In contrast, the secretion of IL-12 and IL-6 and the formation of il-12 and il-6 mRNA induced in bone marrow-derived macrophages (BMDMs) by prolonged stimulation with TLR-activating ligands that signal via myddosomes, which also requires the interaction of IRAK2 with TRAF6, were not increased but modestly reduced in HOIL-1[C458S] BMDM. The decreased production of these cytokines correlated with reduced ubiquitylation of IRAK2. Our results establish that changes in HOIL-1-catalysed ester-linked ubiquitylation can promote or reduce cytokine production depending on the ligand, receptor and immune cell and may be explained by differences in the ubiquitylation of IRAK2.


Assuntos
Ésteres/química , Interleucina-18/metabolismo , Macrófagos/imunologia , Linfócitos T Citotóxicos/imunologia , Receptores Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitina/química , Ubiquitinação , Animais , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
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