RESUMO
ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Ripk1D325A/D325A) with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-dependent cell death. Intriguingly, Ripk1D325A/D325A cells die spontaneously when ZBP1-S is deleted, indicating that cell death driven by ZBP1 is under the control of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against autoinflammations.
Assuntos
Morte Celular , Isoformas de Proteínas , Proteínas de Ligação a RNA , Animais , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Camundongos , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Humanos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Camundongos Endogâmicos C57BL , Processamento Alternativo/genética , Células HEK293 , Inflamação/metabolismo , Inflamação/patologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of abnormal protein aggregates, neuronal loss, synaptic dysfunction, and neuroinflammation. Microglia are resident macrophages of the central nervous system (CNS). Evidence has shown that impaired microglial autophagy exerts considerable detrimental impact on the CNS, thus contributing to AD pathogenesis. This review highlights the association between microglial autophagy and AD pathology, with a focus on the inflammatory response, defective clearance, and propagation of Aß and Tau, and synaptic dysfunction. Mechanistically, several lines of research support the roles of microglial receptors in autophagy regulation during AD. In light of accumulating evidence, a strategy for inducing microglial autophagy has great potential in AD drug development.
RESUMO
Necroptosis induction in vitro often requires caspase-8 (Casp8) inhibition by zVAD because pro-Casp8 cleaves RIP1 to disintegrate the necrosome. It has been unclear how the Casp8 blockade of necroptosis is eliminated naturally. Here, we show that pro-Casp8 within the necrosome can be inactivated by phosphorylation at Thr265 (pC8T265). pC8T265 occurs in vitro in various necroptotic cells and in the cecum of TNF-treated mice. p90 RSK is the kinase of pro-Casp8. It is activated by a mechanism that does not need ERK but PDK1, which is recruited to the RIP1-RIP3-MLKL-containing necrosome. Phosphorylation of pro-Casp8 at Thr265 can substitute for zVAD to permit necroptosis in vitro. pC8T265 mimic T265E knockin mice are embryonic lethal due to unconstrained necroptosis, and the pharmaceutical inhibition of RSK-mediated pC8T265 diminishes TNF-induced cecum damage and lethality in mice by halting necroptosis. Thus, phosphorylation of pro-Casp8 at Thr265 by RSK is an intrinsic mechanism for passing the Casp8 checkpoint of necroptosis.
Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Caspase 8/metabolismo , Necroptose , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Animais , Ceco/lesões , Ceco/patologia , Linhagem Celular , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Mutação/genética , Necroptose/efeitos dos fármacos , Especificidade de Órgãos , Fosforilação/efeitos dos fármacos , Fosfotreonina/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between heredity and environment1,2. Here we report that deficiency in SETDB1, a histone methyltransferase that mediates the trimethylation of histone H3 at lysine 9, participates in the pathogenesis of IBD. We found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability3, and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses (retrovirus-like elements with long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.
Assuntos
Instabilidade Genômica , Histona-Lisina N-Metiltransferase/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Necroptose , Células-Tronco/metabolismo , Animais , Histona-Lisina N-Metiltransferase/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Camundongos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Células-Tronco/citologiaRESUMO
Decompression sickness (DCS) is a major concern in diving and space walk. Hyperbaric oxygen (HBO) preconditioning has been proved to enhance tolerance to DCS via nitric oxide. Heat-shock protein (HSP) 70 was also found to have protective effects against DCS. We hypothesized that the beneficial effects of HBO preconditioning on DCS was related to levels of elevated HSP70. HSPs (70, 27 and 90) expressed in tissues of spinal cord and lung in rats was detected at different time points following HBO exposure by Western blot. HSP27 and HSP90 showed a slight but not significant increase after HBO. HSP70 increased and reached highest at 18 h following exposure before decreasing. Then rats were exposed to HBO and subjected to simulated air dive and rapid decompression to induce DCS 18 h after HBO. The severity of DCS, along with levels of HSP70 expression, as well as the extent of oxidative and apoptotic parameters in the lung and spinal cord were compared among different groups of rats pretreated with HBO, HBO plus NG-nitro-l-arginine-methyl ester (l-NAME), HBO plus quercetin or normobaric air. HBO preconditioning significantly reduced the morbidity of DCS (from 66.7% to 36.7%), reduced levels of oxidation (malondialdehyde, 8-hydroxyguanine and hydrogen peroxide) and apoptosis (caspase-3 and -9 activities and the number of apoptotic cells). l-NAME or quercetin eliminated most of the beneficial effects of HBO on DCS, and counteracted the stimulation of HSP70 by HBO. Bubbles in pulmonary artery were detected using ultrasound imaging to observe the possible effect of HBO preconditioning on DCS bubble formation. The amounts of bubbles in rats pretreated with HBO or air showed no difference. These results suggest that HSP70 was involved in the beneficial effects of HBO on DCS in rats, suspected be by the antioxidation and antiapoptosis effects.
Assuntos
Doença da Descompressão/patologia , Doença da Descompressão/fisiopatologia , Proteínas de Choque Térmico HSP70/metabolismo , Oxigenoterapia Hiperbárica , Animais , Western Blotting , Perfilação da Expressão Gênica , Pulmão/química , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Medula Espinal/química , Medula Espinal/patologiaAssuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular/fisiologia , Oxigenoterapia Hiperbárica/efeitos adversos , Convulsões/fisiopatologia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Eletroencefalografia/métodos , Indazóis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Convulsões/etiologia , Fatores de TempoRESUMO
INTRODUCTION: Hydrogen (H2) has been reported to be effective in the treatment of oxidative injury, which plays an important role in the process of decompression sickness (DCS). This study was designed to test whether H2-rich saline (saline saturated with molecular hydrogen) protected rats against DCS. METHODS: Models of DCS were induced in male Sprague-Dawley rats weighing 300-310 g. H2-rich (0.86 mmol x L(-1)) saline was administered intraperitoneally (10 ml x kg(-1)) at 24 h, 12 h, immediately before compression, and right after fast decompression. RESULTS: H2-rich saline significantly decreased the incidence of DCS from 67.57 to 35.14% and partially counteracted the increases in the total concentration of protein in the bronchoalveolar lavage from 0.33 +/- 0.05 to 0.14 +/- 0.01 mg x ml(-1) (mean +/- SD; P < 0.05), myeloperoxidase activity from 0.86 +/- 0.16 to 0.44 +/- 0.13 U/g, levels of malondialdehyde (MDA) from 0.80 +/- 0.10 to 0.48 +/- 0.05 nmol x mg(-1), 8-hydroxydeoxyguanosine from 253.7 +/- 9.3 to 191.2 +/- 4.8 pg x mg(-1) in the lungs, and MDA level from 1.77 +/- 0.20 to 0.87 +/- 0.23 nmol x mg(-1) in the spinal cord in rat DCS models. The histopathology results also showed that H2-rich saline ameliorated DCS injuries. DISCUSSION: It is concluded that H2-rich saline may have a protective effect against DCS, possibly due to its antioxidant action.
Assuntos
Doença da Descompressão/prevenção & controle , Hidrogênio/farmacologia , Cloreto de Sódio/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Análise de Variância , Animais , Líquido da Lavagem Broncoalveolar/química , Córtex Cerebral/metabolismo , Distribuição de Qui-Quadrado , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Hidrogênio/administração & dosagem , Injeções Intraperitoneais , Pulmão/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , Peroxidase/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio/administração & dosagem , Medula Espinal/metabolismoRESUMO
OBJECTIVE: To investigate the ability of acidogenicity of S. mutans (serotype C) strains isolated from the people with different caries experience. METHODS: Same density solutions of all isolated S. mutans were made and cultured in different pH TPPE liquid for the same period of time. Terminal pH of the solutions was measured. The values of delta pH were compared. RESULTS: Significant difference of acidogenicity was observed between the strains of different genotypes isolated from the same person. The ratio of high acidogenicity isolates harbored in caries-active people was greater than that of caries-free people; a significant difference was noted (P<0.05). CONCLUSION: The high cariogenicity of isolated S. mutans strains of caries-active people shows a close relationship with the high acidogenicity of the isolated S. mutans (serotype C) strains.