RESUMO
Vitamin K refers to a group of structurally similar vitamins that are essential for proper blood coagulation, as well as bone and cardiovascular health. Previous studies have indicated that vitamin K may also have anti-inflammatory properties, although the underlying mechanisms of its anti-inflammatory effects remain unclear. The NLRP3 inflammasome is a multiprotein complex, and its activation leads to IL-1ß and IL-18 secretion and contributes to the pathogenesis of various human inflammatory diseases. Here, we show that synthetic vitamins K3 and K4 are selective, potent inhibitors of the NLRP3 inflammasome and specifically block the interaction between NLRP3 and ASC, thereby inhibiting NLRP3 inflammasome assembly. Moreover, we show that treatment with vitamin K3 or K4 attenuates the severity of inflammation in a mouse model of peritonitis. Our results demonstrate that vitamins K3 and K4 exert their anti-inflammatory effects by inhibiting NLRP3 inflammasome activation and indicate that vitamin K supplementation may be a treatment option for NLRP3-associated inflammatory diseases.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Inflamação/tratamento farmacológico , Inflamação/patologia , Interleucina-1beta , Camundongos , Camundongos Endogâmicos C57BL , Vitamina K/farmacologiaRESUMO
Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori's anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Gotosa/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diterpenos do Tipo Caurano/farmacologia , Quinases Relacionadas a NIMA/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Peritonite/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Artrite Gotosa/genética , Artrite Gotosa/imunologia , Artrite Gotosa/patologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Diterpenos do Tipo Caurano/isolamento & purificação , Regulação da Expressão Gênica , Humanos , Inflamassomos/química , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamação , Isodon/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Peritonite/genética , Peritonite/imunologia , Peritonite/patologia , Extratos Vegetais/química , Ligação Proteica , Transdução de SinaisRESUMO
Tenuigenin (TNG) has been reported to have various pharmacological activities, such as anti-oxidative and anti-inflammatory activities. However, the protective effects of TNG on lipopolysaccharides (LPS)-induced acute kidney injury (AKI) are still not clear. The aim of this study was to investigate the protective effects and mechanism of TGN on LPS-induced AKI in mice. The kidney histological change, levels of blood urea nitrogen (BUN), and creatinine were measured to assess the protective effects of TNG on LPS-induced AKI. The levels of TNF-α, IL-1ß, and IL-6 in serum and kidney tissues were detected by ELISA. The extent of nuclear factor kappa-B (NF-κB) p65 and the expression of Toll-like receptor-4 (TLR4) were detected by western blot analysis. The results showed that TNG markedly attenuated the histological alterations, BUN and creatinine levels in kidney. TNG also suppressed LPS-induced TNF-α, IL-1ß, and IL-6 production. Furthermore, the expression of TLR4 and NF-κB activation induced by LPS were markedly inhibited by TNG. In conclusion, this study demonstrated that TNG protected against LPS-induced AKI by inhibiting TLR4/NF-κB signaling pathway.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Medicamentos de Ervas Chinesas/farmacologia , Lipopolissacarídeos/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/fisiopatologia , Animais , Citocinas/biossíntese , Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
NOD2 functions as an intracellular sensor for microbial pathogen and plays an important role in epithelial defense. The loss-of-function mutation of NOD2 is strongly associated with human Crohn's disease (CD). However, the mechanisms of how NOD2 maintains the intestinal homeostasis and regulates the susceptibility of CD are still unclear. Here we found that the numbers of intestinal intraepithelial lymphocytes (IELs) were reduced significantly in Nod2(-/-) mice and the residual IELs displayed reduced proliferation and increased apoptosis. Further study showed that NOD2 signaling maintained IELs via recognition of gut microbiota and IL-15 production. Notably, recovery of IELs by adoptive transfer could reduce the susceptibility of Nod2(-/-) mice to the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Our results demonstrate that recognition of gut microbiota by NOD2 is important to maintain the homeostasis of IELs and provide a clue that may link NOD2 variation to the impaired innate immunity and higher susceptibility in CD.
Assuntos
Epitélio/imunologia , Homeostase , Intestinos/imunologia , Intestinos/microbiologia , Linfócitos/metabolismo , Microbiota , Proteína Adaptadora de Sinalização NOD2/metabolismo , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Suplementos Nutricionais , Suscetibilidade a Doenças , Epitélio/efeitos dos fármacos , Epitélio/patologia , Sistema Hematopoético/efeitos dos fármacos , Sistema Hematopoético/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Interleucina-15/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Baço/citologia , Timo/citologia , Ácido TrinitrobenzenossulfônicoRESUMO
Omega-3 fatty acids (ω-3 FAs) have potential anti-inflammatory activity in a variety of inflammatory human diseases, but the mechanisms remain poorly understood. Here we show that stimulation of macrophages with ω-3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1ß secretion. In addition, G protein-coupled receptor 120 (GPR120) and GPR40 and their downstream scaffold protein ß-arrestin-2 were shown to be involved in inflammasome inhibition induced by ω-3 FAs. Importantly, ω-3 FAs also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced type 2 diabetes model. Our results reveal a mechanism through which ω-3 FAs repress inflammation and prevent inflammation-driven diseases and suggest the potential clinical use of ω-3 FAs in gout, autoinflammatory syndromes, or other NLRP3 inflammasome-driven inflammatory diseases.