RESUMO
Aberrant inflammasome activation contributes to the pathogenesis of various human diseases, including atherosclerosis, gout, and metabolic disorders. Elucidation of the underlying mechanism involved in the negative regulation of the inflammasome is important for developing new therapeutic targets for these diseases. Here, we showed that Raf kinase inhibitor protein (RKIP) negatively regulates the activation of the NLRP1, NLRP3, and NLRC4 inflammasomes. RKIP deficiency enhanced caspase-1 activation and IL-1ß secretion via NLRP1, NLRP3, and NLRC4 inflammasome activation in primary macrophages. The overexpression of RKIP in THP-1 cells inhibited NLRP1, NLRP3, and NLRC4 inflammasome activation. RKIP-deficient mice showed increased sensitivity to Alum-induced peritonitis and Salmonella typhimurium-induced inflammation, indicating that RKIP inhibits NLRP3 and NLRC4 inflammasome activation in vivo. Mechanistically, RKIP directly binds to apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and competes with NLRP1, NLRP3, or NLRC4 to interact with ASC, thus interrupting inflammasome assembly and activation. The depletion of RKIP aggravated inflammasome-related diseases such as monosodium urate (MSU)-induced gouty arthritis and high-fat diet (HFD)-induced metabolic disorders. Furthermore, the expression of RKIP was substantially downregulated in patients with gouty arthritis or type 2 diabetes (T2D) compared to healthy controls. Collectively, our findings suggest that RKIP negatively regulates NLRP1, NLRP3, and NLRC4 inflammasome activation and is a potential therapeutic target for the treatment of inflammasome-related diseases.
Assuntos
Artrite Gotosa/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inflamassomos/imunologia , Macrófagos/imunologia , Peritonite/imunologia , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/metabolismo , Peritonite/patologia , Proteína de Ligação a Fosfatidiletanolamina/genética , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismoRESUMO
Adipose tissue macrophages (ATMs) regulate the occurrence of obesity and its related diseases. Here, we found that serine/threonine protein kinase 24 (Stk24) expression is downregulated significantly in ATMs in obese subjects or obese subjects with type 2 diabetes and mice fed a high-fat diet (HFD). We further identified that glucolipotoxicity downregulated Stk24 expression in ATMs. Stk24-deficient mice develop severe HFD-induced metabolic disorders and insulin insensitivity. Mechanistically, Stk24 intervenes in NLRP3 inflammasome assembly in ATMs by associating directly with NLRP3, decreasing interleukin-1ß (IL-1ß) secretion. Accordingly, Stk24 deficiency in the hematopoietic system promotes NLRP3 inflammasome activation, which contributes to exacerbation of metabolic disorders. Intriguingly, Stk24 expression correlates negatively with body mass index (BMI) and the levels of glucose, cholesterol, triglycerides, and low-density lipoprotein in human subjects. These findings provide insights into the function and clinical implications of Stk24 in obesity-mediated metabolic disorders.
Assuntos
Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/genética , Proteínas Serina-Treonina Quinases/uso terapêutico , Animais , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; however, IFNs also induce negative regulators that attenuate the antiviral response. Here, we show that both viral and bacterial invasion downregulate Nuclear Dbf2-related kinase 1 (NDR1) expression via the type I IFN signaling pathway. NDR1 promotes the virus-induced production of type I IFN, proinflammatory cytokines and ISGs in a kinase-independent manner. NDR1 deficiency also renders mice more susceptible to viral and bacterial infections. Mechanistically, NDR1 enhances STAT1 translation by directly binding to the intergenic region of miR146a, thereby inhibiting miR146a expression and liberating STAT1 from miR146a-mediated translational inhibition. Furthermore, STAT1 binds to the miR146a promoter, thus decreasing its expression. Together, our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections.
Assuntos
Bronquiolite Viral/genética , Retroalimentação Fisiológica , Herpesvirus Humano 1/genética , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição STAT1/genética , Vírus da Estomatite Vesicular Indiana/genética , Animais , Bronquiolite Viral/imunologia , Bronquiolite Viral/virologia , Estudos de Casos e Controles , Criança , Regulação da Expressão Gênica , Células HEK293 , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Interferon-alfa/genética , Interferon-alfa/imunologia , Interferon beta/genética , Interferon beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/imunologia , Biossíntese de Proteínas , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/imunologia , Células RAW 264.7 , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/imunologia , Fator de Transcrição STAT1/imunologia , Transdução de Sinais , Vírus da Estomatite Vesicular Indiana/imunologiaRESUMO
A novel pretreatment process was developed to achieve valorization of bamboo components into digestible cellulose, degraded sugars and lignin. In this case, bamboo was pretreated with 60% γ-valerolactone (GVL)/40% water containing 0.05mol/L H2SO4, yielding solid fraction rich in cellulose. The resulting liquor was further treated with the addition of NaCl and ultrasound, resulting in water phase rich in degraded sugars and GVL phase containing lignin, which was easy to recover. Results showed that the enzymatic hydrolysis was enhanced by 6.7-fold after treatment as compared to the control. The degraded sugars released in water phase contained monosaccharides (70.72-160.47g/kg) together with oligo- and polysaccharides (46.4-181.85g/kg). The lignin obtained had high purity, low molecular weight (1820-2970gmol-1) and low polydispersity (1.93-1.98). The present study creates a novel pretreatment process for the conversion of Gramineae biomass into useful feedstocks with potential applications in the fields of fuels, chemicals and polymers.