RESUMO
SIRT6, a key member of the sirtuin family, plays a pivotal role in regulating a number of vital biological processes, including energy metabolism, oxidative stress, and immune system modulation. Nevertheless, the function of SIRT6 in bony fish, particularly in the context of antiviral immune response, remains largely unexplored. In this study, a sirt6 was cloned and characterized in a commercial fish, the Chinese perch (Siniperca chuatsi). The SIRT6 possesses conserved SIR2 domain with catalytic core region when compared with other vertebrates. Tissue distribution analysis indicated that sirt6 was expressed in all detected tissues, and the sirt6 was significantly induced following infection of infectious haemorrhagic syndrome virus (IHSV). The overexpression of SIRT6 resulted in significant upregulation of interferon-stimulated genes (ISGs), such as viperin, mx, isg15, irf3 and ifp35, and inhibited viral replication. It was further found that SIRT6 was located in nucleus and could enhance the expression of ISGs induced by type I and II IFNs. These findings may provide new information in relation with the function of SIRT6 in vertebrates, and with viral prevention strategy development in aquaculture.
Assuntos
Sequência de Aminoácidos , Doenças dos Peixes , Proteínas de Peixes , Regulação da Expressão Gênica , Imunidade Inata , Percas , Filogenia , Infecções por Rhabdoviridae , Sirtuínas , Animais , Sirtuínas/genética , Sirtuínas/imunologia , Sirtuínas/metabolismo , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas de Peixes/química , Imunidade Inata/genética , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Regulação da Expressão Gênica/imunologia , Percas/imunologia , Alinhamento de Sequência/veterinária , Perfilação da Expressão Gênica/veterináriaRESUMO
BACKGROUND: Binding IgE to a cognate allergen causes aggregation of Fcε receptor I (FcεRI) in mast cells, resulting in activation of receptor-associated Src family tyrosine kinases, including Lyn and Syk. Protein tyrosine phosphatase, receptor type C (PTPRC), also known as CD45, has emerged as a positive regulator of FcεRI signaling by dephosphorylation of the inhibitory tyrosine of Lyn. OBJECTIVE: Sirtuin 6 (Sirt6), a NAD+-dependent deacetylase, exhibits an anti-inflammatory property. It remains to be determined, however, whether Sirt6 attenuates mast cell-associated diseases, including anaphylaxis. METHODS: FcεRI signaling and mast cell degranulation were measured after IgE cross-linking in murine bone marrow-derived mast cells (BMMCs) and human cord blood-derived mast cells. To investigate the function of Sirt6 in mast cell activation in vivo, we used mast cell-dependent animal models of passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA). RESULTS: Sirt6-deficient BMMCs augmented IgE-FcεRI-mediated signaling and degranulation compared to wild-type BMMCs. Reconstitution of mast cell-deficient KitW-sh/W-sh mice with BMMCs received from Sirt6 knockout mice developed more severe PSA and PCA compared to mice engrafted with wild-type BMMCs. Similarly, genetic overexpression or pharmacologic activation of Sirt6 suppressed mast cell degranulation and blunted responses to PCA. Mechanistically, Sirt6 deficiency increased PTPRC transcription via acetylating histone H3, leading to enhanced aggregation of FcεRI in BMMCs. Finally, we recapitulated the Sirt6 regulation of PTPRC and FcεRI signaling in human mast cells. CONCLUSIONS: Sirt6 acts as a negative regulator of FcεRI signaling cascade in mast cells by suppressing PTPRC transcription. Activation of Sirt6 may therefore represent a promising and novel therapeutic strategy for anaphylaxis.
Assuntos
Anafilaxia/imunologia , Mastócitos/imunologia , Receptores de IgE/imunologia , Sirtuínas/imunologia , Animais , Células da Medula Óssea/citologia , Sangue Fetal/citologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Sirtuínas/genéticaRESUMO
COVID-19 is a pandemic requiring immediate solution for treatment because of its complex pathophysiology. Exploration of novel targets and thus treatment will be life savers which is the need of the hour. 2 host factors- TMPRSS2 and ACE2 are responsible for the way the virus will enter and replicate in the host. Also NRF2 is an important protein responsible for its anti-inflammatory role by multiple mechanisms of action like inhibition of NF-kB, suppression of pro-inflammatory genes, etc. NRF2 is deacetylated by Sirtuins and therefore both have a direct association. Absence of SIRT indicates inhibition of NRF2 expression and thus no anti-oxidative and anti-inflammatory protection for the cell. Therefore, we propose that NRF2 activators and/or SIRT activators can be evaluated to check their efficacy in ameliorating the symptoms of COVID-19.
Assuntos
COVID-19/imunologia , Fator 2 Relacionado a NF-E2/imunologia , SARS-CoV-2/imunologia , Sirtuínas/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Sirtuínas/metabolismo , Ligação ViralRESUMO
Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP-Seq) and assay for transposase-accessible chromatin using sequencing (ATAC)-seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase-2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5-/- airway macrophages but not bone marrow-derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll-like receptor (TLR)-3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild-type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR-3 activation.
Assuntos
Metabolismo Energético/imunologia , Regulação da Expressão Gênica/imunologia , Fatores Reguladores de Interferon/imunologia , Macrófagos/imunologia , Sistema Respiratório/citologia , Animais , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Metabolismo Energético/genética , Feminino , Hexoquinase/genética , Hexoquinase/imunologia , Hexoquinase/metabolismo , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sirtuínas/genética , Sirtuínas/imunologia , Sirtuínas/metabolismo , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismoRESUMO
We studied the effect of KE and AED peptides on the expression of sirtuin-1, sirtuin-6, collagen I, cytokines (IL-1, TGF-ß), and transcription factor NF-κB in human skin fibroblasts during their replicative aging. Immunocytochemical analysis and confocal microscopy showed that KE peptide reduces the synthesis of factors of the inflammatory response IL-1, NF-κB, and TGF-ß and stimulates the synthesis of sirtuin-6. KE peptide normalizes the immunological function of human skin fibroblasts during their aging. AED peptide activates the synthesis of sirtuin-1, sirtuin-6, and collagen I in human skin fibroblasts during their replicative aging, which attests to its geroprotective effect.
Assuntos
Antioxidantes/farmacologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Oligopeptídeos/farmacologia , Antioxidantes/síntese química , Senescência Celular/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia , Feminino , Fibroblastos/citologia , Fibroblastos/imunologia , Humanos , Fatores Imunológicos/síntese química , Interleucina-1/genética , Interleucina-1/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Oligopeptídeos/síntese química , Cultura Primária de Células , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/imunologia , Sirtuínas/genética , Sirtuínas/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologiaRESUMO
Age-associated dysfunction of retinal pigment epithelial cells (RPEs) is considered to be the initial trigger of retinal diseases such as age-related macular degeneration. Although autophagy is upregulated in RPEs during the course of aging, little is known about how autophagy is regulated and its functional role in RPEs. In this study, we found that expression of Sirtuin 6 (SIRT6) and autophagic markers are upregulated in RPEs of aged mice where subretinal deposition of amyloid-ß is accumulated and in amyloid-ß stimulated RPEs. In addition, gain and loss-of-function studies confirmed the positive role of SIRT6 in regulating autophagy. Interesting, inhibition of autophagy attenuates amyloid-ß stimulated inflammatory response in RPEs. Collectively, our findings uncover the autophagy modulated by SIRT6 may be a proinflammatory mechanism for amyloid-ß induced RPE dysfunction.
Assuntos
Peptídeos beta-Amiloides/imunologia , Autofagia/imunologia , Células Epiteliais/imunologia , Mediadores da Inflamação/imunologia , Epitélio Pigmentado da Retina/imunologia , Retinite/imunologia , Sirtuínas/imunologia , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia , Retinite/induzido quimicamente , Retinite/patologiaRESUMO
Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess-linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation.
Assuntos
Diabetes Mellitus Tipo 2/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Mitocôndrias/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Obesidade/imunologia , Animais , Diabetes Mellitus Tipo 2/patologia , Ingestão de Energia , Humanos , Inflamação/patologia , Mitocôndrias/patologia , Sirtuínas/imunologiaRESUMO
Crop destruction by the hemibiotrophic rice pathogen Magnaporthe oryzae requires plant defence suppression to facilitate extensive biotrophic growth in host cells before the onset of necrosis. How this is achieved at the genetic level is not well understood. Here, we report that a M. oryzae sirtuin, MoSir2, plays an essential role in rice defence suppression and colonization by controlling superoxide dismutase (SOD) gene expression. Loss of MoSir2 function in Δsir2 strains did not affect appressorial function, but biotrophic growth in rice cells was attenuated. Compared to wild type, Δsir2 strains failed to neutralize plant-derived reactive oxygen species (ROS) and elicited robust defence responses in rice epidermal cells that included elevated pathogenesis-related gene expression and granular depositions. Deletion of a SOD-encoding gene under MoSir2 control generated Δsod1 deletion strains that mimicked Δsir2 for impaired rice defence suppression, confirming SOD activity as a downstream output of MoSir2. In addition, comparative protein acetylation studies and forward genetic analyses identified a JmjC domain-containing protein as a likely target of MoSir2, and a Δsir2 Δjmjc double mutant was restored for MoSOD1 expression and defence suppression in rice epidermal cells. Together, this work reveals MoSir2 and MoJmjC as novel regulators of early rice cell infection.
Assuntos
Proteínas Fúngicas/imunologia , Magnaporthe/enzimologia , Oryza/microbiologia , Doenças das Plantas/microbiologia , Sirtuínas/imunologia , Proteínas Fúngicas/genética , Interações Hospedeiro-Patógeno , Magnaporthe/genética , Magnaporthe/imunologia , Magnaporthe/fisiologia , Oryza/imunologia , Doenças das Plantas/imunologia , Proteínas de Plantas/imunologia , Sirtuínas/genéticaRESUMO
OBJECTIVE: Sirtuin 6 (SIRT-6) is an NAD(+) -dependent deacetylase and mono-ADP-ribosyltransferase. It is known to interfere with the NF-κB signaling pathway and thereby has an antiinflammatory function. Due to the central role of NF-κB in rheumatoid arthritis (RA) development, we undertook this study to test our hypothesis that SIRT-6 could have antiarthritic effects. METHODS: An adenovirus containing SIRT-6 complementary DNA (Ad-SIRT6) was used to deliver SIRT-6 to human RA fibroblast-like synoviocytes in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via bilateral intraarticular injections into the ankle joints. RESULTS: In vitro experiments demonstrated that SIRT-6 overexpression suppressed NF-κB target gene expression induced by tumor necrosis factor α. SIRT-6 overexpression inhibited osteoclast differentiation induced by macrophage colony-stimulating factor and RANKL in bone marrow-derived macrophages. Mice with CIA had an increased incidence of disease and developed arthritis in the hind paws. In contrast, mice injected with Ad-SIRT6 showed attenuated severity of arthritis based on clinical scores, hind paw thickness, and radiographic and pathologic findings. Moreover, the injection of Ad-SIRT6 down-regulated local and systemic levels of proinflammatory cytokines. After induction of CIA, mice injected with Ad-SIRT6 showed significantly decreased arthritis severity, from the onset of clinical signs to the end of the study. CONCLUSION: These results suggest that blocking the NF-κB pathway by SIRT-6 in rheumatoid joints reduces both the inflammatory response and tissue destruction. Therefore, the development of an immunoregulatory strategy based on SIRT-6 may have therapeutic potential for the treatment of RA.
Assuntos
Artrite Experimental/terapia , Artrite Reumatoide/imunologia , NF-kappa B/imunologia , Sirtuínas/fisiologia , Membrana Sinovial/citologia , Acetilação , Animais , Artrite Experimental/imunologia , Diferenciação Celular , Células Cultivadas , Técnicas de Transferência de Genes , Humanos , Mediadores da Inflamação/imunologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Osteoclastos/citologia , Transdução de Sinais , Sirtuínas/genética , Sirtuínas/imunologia , Membrana Sinovial/imunologia , Fator de Necrose Tumoral alfa/imunologia , Regulação para CimaRESUMO
Rationale: Hosts defend against viral infection by sensing viral pathogen-associated molecular patterns and activating antiviral innate immunity through TBK1-IRF3 signaling. However, the underlying molecular mechanism remains unclear. Methods: SiRNAs targeting Sirt1-7 were transfected into macrophages to screen the antiviral function. Sirt5 deficient mice or macrophages were subjected to viral infection to assess in vivo and in vitro function of Sirt5 by detecting cytokines, viral replicates and survival rate. Immunoprecipitation, WesternBlot and luciferase reporter assay were used to reveal molecular mechanism. Results: In this study, we functionally screened seven Sirtuin family members, and found that Sirtuin5 (Sirt5) promotes antiviral signaling and responses. Sirt5 deficiency leads to attenuated antiviral innate immunity in vivo and in vitro upon viral infection by decreasing TBK1-IRF3 activation and type I IFN production. Sirt5 overexpression increased antiviral innate immunity. Mechanism investigation revealed that Sirt5 interacts with DDX3 and demalonylates DDX3, which is critical for TBK1-IRF3 activation. Mutation of the demalonylation lysine sites (K66, K130, and K162) of DDX3 increased ifnß transcription. Furthermore, the acetylation on lysine 118 of DDX3 positively regulated ifnß transcription, whereas Sirt5 could not deacetylate this site. Conclusion: Sirt5 promotes anti- RNA and DNA virus innate immune responses by increasing TBK1 signaling through demalonylating DDX3, which identifies a novel regulatory pathway of antiviral innate immune response.
Assuntos
RNA Helicases DEAD-box/imunologia , Imunidade Inata , Macrófagos/imunologia , Sirtuínas/imunologia , Estomatite Vesicular/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Animais , RNA Helicases DEAD-box/genética , Células HEK293 , Humanos , Lipoilação/genética , Lipoilação/imunologia , Macrófagos/virologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Células RAW 264.7 , Sirtuínas/genética , Estomatite Vesicular/genética , Vírus da Estomatite Vesicular Indiana/genéticaRESUMO
The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF-kappaB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF-kappaB system in aging and immune responses. Adler et al showed that the NF-kappaB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al studying HIV-1 infection and subsequent immune deficiency process demonstrated that HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NF-kappaB complex. As a consequence, the transactivation efficiency of the NF-kappaB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF-kappaB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF-kappaB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.
Assuntos
Envelhecimento/imunologia , Regulação da Expressão Gênica , NF-kappa B/imunologia , Sirtuínas/imunologia , Acetilação , Animais , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunidade Inata , Inflamação/imunologia , Camundongos , Ratos , Transdução de Sinais/imunologia , Sirtuína 1 , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologiaRESUMO
Adipose tissue inflammation is a reproducible feature of obesity and obesity-linked insulin resistance. Although sirtuin 6 (Sirt6) deficiency has previously been implicated in diet-induced obesity and systemic insulin resistance, the adipocyte-specific role of Sirt6 in the regulation of adipose tissue inflammation and systemic metabolic dysfunction in mice fed normal chow and in humans remains elusive. Here, using Adipoq-Cre-mediated adipocyte-specific Sirt6 knockout (aS6KO) mice, we explored whether adipocyte Sirt6 inhibits adipose tissue inflammation and its underlying mechanism. aS6KO mice fed normal chow gained more body weight and fat mass than wild-type mice and exhibited glucose intolerance and systemic insulin resistance. Measurement of plasma and tissue cytokines and flow cytometric analysis of adipose stromal vascular cells indicated a decrease in alternatively activated M2 macrophages in the adipose tissue of aS6KO mice. Mechanistically, Sirt6 regulated the expression of the canonical type 2 cytokine IL-4 by adipocytes in a cell autonomous manner, which in turn affects M2 macrophage polarization. Consistent with animal experimental data, the degree of obesity and insulin resistance demonstrated by the body mass index, fasting blood glucose and HbA1c correlated negatively with the expression of Sirt6 in human visceral fat tissues. Collectively, these results suggest that adipocyte Sirt6 regulates body weight gain and insulin sensitivity independent of diet, and the increased IL-4 production by Sirt6 and resultant M2 polarization of adipose tissue macrophages may attenuate proinflammatory responses in adipose tissue.
Assuntos
Resistência à Insulina/imunologia , Interleucina-4/imunologia , Macrófagos/imunologia , Sirtuínas/imunologia , Tecido Adiposo/imunologia , Adiposidade , Animais , Células Cultivadas , Humanos , Inflamação/imunologia , Macrófagos/citologia , Camundongos , Obesidade/imunologiaRESUMO
Osteoarthritis (OA) is the most prevalent form of human arthritis which is characterized by the degradation of cartilage and inflammation. As a rare Sirt6 activator, cyanidin is the major component of anthocyanins commonly found in the Mediterranean diet, and increasing evidence has shown that cyanidin exhibits anti-inflammatory effects in a variety of diseases. However, the anti-inflammatory effects of cyanidin on OA have not been reported. In the present study, we identified that cyanidin treatment could strongly suppress the expression of NO, PGE2, TNF-α, IL-6, iNOs, COX-2, ADAMTS5 and MMP13, and reduce the degradation of aggrecan and collagen II in IL-1ß-induced human OA chondrocytes, indicating the anti-inflammatory effect of cyanidin. Further investigation of the mechanism involved revealed that cyanidin could upregulate the Sirt6 level in a dose-dependent manner and Sirt6 silencing abolished the effect of cyanidin in IL-1ß-stimulated human OA chondrocytes, indicating a stimulatory effect of cyanidin on Sirt6 activation. Meanwhile, we found that cyanidin could inhibit the NF-κB pathway in IL-1ß-stimulated human OA chondrocytes and its effect may to some extent depend on Sirt6 activation, suggesting that cyanidin may exert a protective effect through regulating the Sirt6/NF-κB signaling axis. Moreover, the in vivo study also proved that cyanidin ameliorated the development of OA in surgical destabilization of the medial meniscus (DMM) mouse OA models. In conclusion, these results demonstrate that cyanidin may have therapeutic potential for the treatment of OA.
Assuntos
Antocianinas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , NF-kappa B/imunologia , Osteoartrite/tratamento farmacológico , Sirtuínas/imunologia , Animais , Condrócitos/efeitos dos fármacos , Condrócitos/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Metaloproteinase 13 da Matriz , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Osteoartrite/genética , Osteoartrite/imunologia , Sirtuínas/genéticaRESUMO
Hydroxytyrosol acetate (HT-AC), a polyphenolic compound in olive oil, exerts an anti-inflammatory effect on murine collagen-induced arthritis. However, the effect of HT-AC on inflammatory response in cardiovascular disease remains unclear. Thus, in this study, we aimed to investigate the effect of HT-AC on the inflammation response of vascular endothelial cells and the related molecular mechanism. Our results showed that HT-AC inhibited the inflammatory response in hypercholesterolemic mice and tumor necrosis factor (TNF)-stimulated HUVECs. Meanwhile, HT-AC also up-regulated SIRT6 expression in hypercholesterolemic mice and HUVECs. To further investigate whether SIRT6 is involved in the regulation of endothelial inflammatory response by HT-AC, endothelium-specific Sirt6 knockout (Sirt6endo-/-) mice were used. Our study found that Sirt6endo-/- abolished the inhibition of inflammatory response by HT-AC in the thoracic aorta of hypercholesterolemic mice. In vitro study also showed that knockdown of SIRT6 reduced the inhibition of inflammatory response by HT-AC, whereas overexpression of SIRT6 augmented the inhibition of inflammatory response by HT-AC in HUVECs. Further study demonstrated that HT-AC exerts its anti-inflammatory effect partly via the SIRT6-mediated PKM2 signaling pathway. In addition, HT-AC inhibited TNF-induced inflammatory response through the TNF receptor superfamily member 1A (TNFRSF1A) signaling pathway. These findings indicate that HT-AC regulates the vascular endothelial inflammatory response partly through the TNFRSF1A/SIRT6/PKM2-mediated signaling pathway.
Assuntos
Acetatos/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Catecóis/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Piruvato Quinase/imunologia , Sirtuínas/imunologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Células Endoteliais/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piruvato Quinase/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/genéticaRESUMO
BACKGROUND: The activation of tumour-associated macrophages (TAMs) contributes to the progression of hepatocellular carcinoma (HCC). SIRT4 acts as a tumour suppressor of tumour growth by regulating cell metabolism, inflammation, and anti-tumourigenesis. However, the involvement of SIRT4 in the activation of TAMs is unknown. Based on previous findings, the expression of SIRT4 in distinct groups of TAMs as well as the effect of SIRT4 silencing on macrophage polarization was investigated. METHODS: The expression of SIRT4 in HCC tissues and peritumour tissues was tested by qRT-PCR, western blotting and histological analysis. A Kaplan-Meier survival curve was generated based on the expression of SIRT4 in the HCC samples. Next, immunofluorescence staining was used to evaluate distinct groups of TAMs in human HCC samples, and the expression of SIRT4 in M1 and M2 TAMs was examined by flow cytometry. A homograft mouse model was used to assess the effect of SIRT4 silencing in TAMs on the development of HCC cells. RESULTS: SIRT4 was significantly downregulated in HCC tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients. We further found that downregulation of SIRT4 was associated with increased macrophage infiltration and a high ratio of M2/M1 macrophages in HCC peritumour tissues. Using gene interference, we found that SIRT4 silencing in TAMs significantly modulated the alternative activation of macrophages and promoted in vitro and in vivo HCC cell growth. Mechanistically, we revealed that HCM restricted the expression of SIRT4 in macrophages and promoted alternative activation of macrophages via the FAO-PPARδ-STAT3 axis. Furthermore, we also revealed that elevated MCP-1 expression induced by SIRT4 downregulation was responsible for increased TAM infiltration in peritumour tissues. CONCLUSIONS: Overall, our results demonstrate that downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. These results could provide a new therapeutic target for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Proteínas Mitocondriais/metabolismo , PPAR delta/metabolismo , Sirtuínas/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Ativação de Macrófagos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Mitocondriais/imunologia , PPAR delta/genética , PPAR delta/imunologia , Transdução de Sinais , Sirtuínas/imunologia , Células THP-1 , Análise Serial de TecidosRESUMO
Piceatannol (PIC) is a natural hydroxylated analog of resveratrol (RSV) and considered as a potential metabolic regulator. The purpose of this study was to compare the effects of PIC and RSV on parameters affecting inflammation, oxidative stress, and sirtuins (Sirt). Male C57BL/6J mice, 20 weeks old, were assigned to the following groups; (1) lean control, (2) high-fat diet control (HF), (3) HF_PIC, and (4) HF_RSV. Oral administration of PIC and RSV (10 mg/kg/day) for 4 weeks improved glucose control as shown by decreasing levels of area under the curve (AUC) during the oral glucose tolerance test compared with HF group. PIC improved glycemic control by increasing hepatic levels of insulin receptor and AMP-activated protein kinase. PIC increased the levels of Sirt1, Sirt3, and Sirt6 and also increased two downstream targets of Sirt, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and forkhead box O1, in the liver. The inflammatory markers, interleukin (IL)-1 and IL-6, in the liver were downregulated by RSV treatment. Exposure to PIC and RSV significantly lowered hepatic levels of tumor necrosis factor-alpha. However, PIC and RSV treatments showed minimal effects on hepatic markers of oxidative stress. The levels of antioxidant enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), were only increased in livers of RSV-treated mice compared with HF control mice. In conclusion, PIC was superior to an equal concentration of RSV in the regulation of Sirt and its downstream targets as well as insulin signaling-related parameters, while RSV potentially suppressed levels of proinflammatory markers and increased NQO1 protein levels.
Assuntos
Hepatopatias/tratamento farmacológico , Fígado/imunologia , Resveratrol/administração & dosagem , Sirtuínas/genética , Estilbenos/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/imunologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/imunologia , Sirtuínas/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Optimum but balanced food intake maintains healthy growth and disease-free lifespan. However, imbalanced and over-nutrition promotes obesity, diabetes, malignancy, osteoporosis, infectious diseases, etc. In 1936, McCay reported that calorie restriction prevents weight gain and extend lifespan in rodents. In early 1970, Dr. Good at University of Minnesota and Dr. Walford at UCLA began studies in mice by reducing protein and calorie intake and studying their impact on immune function. Dr. Good's group (Jose, Fernandes, Kramer, Cooper, Day, etc.) reported changes in humoral and cellular immunity at present known as innate and adaptive immune function. Later, much interest was devoted by late Dr. Good on studying the role of calorie restriction (CR) and the role of zinc on immunity, particularly their role on aging, autoimmunity, and malignancy. Both functional role of T-cells, NK-cells and B-cells and their interaction during CR was studied extensively. We recently decided to pursue the beneficial effects of n-3 fatty acids (fish oil) with and without CR on controlling autoimmune-disease in NZB x NZW F1 mice. Our results indicated that n-3 FA when fed ad-libitum prolongs lifespan higher than commonly consumed n-6 FA (corn oil) in these mice. Moreover, n-3 FA + CR is found to be more effective than n-6 FA + CR. Some of the beneficial changes by n-3 FA include enhancing antioxidant enzymes and lowering Th-1/Th-2 cytokines, adhesion molecules, COX-2/PGE(2) levels, pro-inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha etc. The decreased pro-inflammatory cytokines were also found to protect against bone loss in OVX mice. Further, Fat-1 transgenic mice (which make n-3 FA endogenously in vivo from n-6 FA) when fed CR revealed decreased NF-kappaB and AP-1 activity and increased expression of life-prolonging gene SIRT1. Also CR and n-3 FA decreases body weight and increases insulin sensitivity, as well. Thus, to prevent obesity decreased calorie intake with n-3 FA supplement is far more effective and may have protection against CVD, malignancy, autoimmunity, and osteoporosis. The CR studies undertaken in primates and recently in humans are showing very encouraging results. In order to understand more precisely the role of diet and nutrition, new approaches exploring the link through nutrigenomics, proteomics and metabolomics may soon provide insight into controlling age-related diseases by following a balanced food intake.
Assuntos
Autoimunidade , Restrição Calórica , Ácidos Graxos Ômega-3/fisiologia , Imunidade , Fenômenos Fisiológicos da Nutrição , Animais , Peso Corporal , Reabsorção Óssea/imunologia , Reabsorção Óssea/metabolismo , Óleo de Milho/administração & dosagem , Citocinas/imunologia , Citocinas/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-6/administração & dosagem , Ácidos Graxos Ômega-6/fisiologia , Óleos de Peixe/administração & dosagem , Óleos de Peixe/metabolismo , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Sirtuína 1 , Sirtuínas/imunologia , Sirtuínas/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Sirtuin 5 (SIRT5) is a member of the family of NAD+-dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, we show that SIRT5 deficiency does not affect immune cell development, cytokine production and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli. Moreover, preclinical models suggest that SIRT5 deficiency does not worsen endotoxemia, Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, Escherichia coli peritonitis, listeriosis, and staphylococcal infection. Altogether, these data support the safety profile in terms of susceptibility to infections of SIRT5 inhibitors under development.
Assuntos
Bactérias/imunologia , Infecções Bacterianas/imunologia , Imunidade Inata , Sirtuínas/deficiência , Animais , Infecções Bacterianas/genética , Camundongos , Camundongos Knockout , Sirtuínas/imunologiaRESUMO
Epigenetic regulators are increasingly recognized as relevant modulators in the immune and nervous system. The class of sirtuins consists of NAD+-dependent histone deacetylases that regulate transcription. Sirtuin family member Sirt1 has already been shown to influence the disease course in an animal model of autoimmune neuroinflammation (experimental autoimmune encephalomyelitis (EAE). A role of Sirt7, a related epigenetic regulator, on immune system regulation has been proposed before, as these mice are more susceptible to develop inflammatory cardiomyopathy. Sirt7-/- animals showed no differences in clinical score compared to wild-type littermates after EAE induction with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, although we found subtle immune alterations at different phases of EAE and decreased survival of newly generated neurons in the hippocampus. Our data indicate that Sirt7 has a slight protective impact on both the adaptive immune system and neurogenesis. However, overall this epigenetic factor is not capable of impacting the acute or chronic phase of neuroinflammation.
Assuntos
Encefalite/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Epigênese Genética , Neurogênese , Sirtuínas/metabolismo , Imunidade Adaptativa , Animais , Proliferação de Células , Encefalite/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Hipocampo/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/imunologia , Sirtuínas/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Osteoarthritis (OA) is a common degenerative joint disease. Inflammation may exaggerate the catabolism and degeneration in the pathogenesis of OA. Hydroxytyrosol (HT) has been used in the management of inflammatory diseases. In addition, reports have revealed that autophagy was a therapeutic target of diseases caused by inflammation. Sirtuin 6 (SIRT6) has also been demonstrated to prevent OA development by reducing both the inflammatory response and chondrocyte senescence. However, the roles of SIRT6 and autophagy in cartilage and its underlying antiinflammatory mechanism are unknown. Therefore, the present study aimed to determine the effects of HT on autophagy and inflammation in chondrocytes, and clarify whether HT regulates the inflammatory response through SIRT6mediated autophagy. The expression of protein and mRNA were determined by western blot analysis and reverse transcriptionquantitative polymerase chain reaction. The production of cytokines was detected by ELISA. It was demonstrated that HT inhibited the levels of interleukin (IL)1ß and IL6 in tumor necrosis factor (TNF)αstimulated chondrocytes in a concentrationdependent manner. In addition, HT promoted cell autophagy and increased the mRNA and protein expression levels of SIRT6 in chondrocytes stimulated with TNF-α. Autophagy inhibitor 3-methyladenine or knockdown of SIRT6 decreased the inhibitory effects of HT on the inflammatory response in chondrocytes. In addition, knockdown of SIRT6 attenuated the expression of microtubule-associated protein 1A/1Blight chain 3 and Beclin1 in chondrocytes. Overall, these findings suggested that HT inhibits the inflammatory response of chondrocytes through SIRT6mediated autophagy. The present study provided a new drug target for the clinical treatment of inflammatory diseases.