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1.
J Toxicol Sci ; 45(10): 625-637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012731

RESUMO

NOD-like receptor protein 3 (NLRP3) is involved in acute lung injury (ALI), but its exact role in phosgene-induced ALI is not clearly understood. The aim of the study is to explore the potential therapeutic effect of NLRP3 inflammasome modulation in the management of phosgene-induced ALI. ALI was induced in rats by phosgene exposure at 8.33 g/m3 for 5 min, 30 hr before intravenous injection of adenovirus-NLRP3 shRNA (Ad/NLRP3-shRNA). The histological changes in the lung were evaluated. Bronchoalveolar lavage fluid (BALF) neutrophils were counted (smear), and protein content was measured using the BCA assay. The wet/dry ratio of lung tissue (W/D) was measured. TUNEL staining for DNA damage was used to indirectly assess pyroptosis. NLRP3 inflammasome was assessed by immunohistochemistry, RT-PCR, western blotting. Cytokines were measured by ELISA. Histological analyses revealed reduced severity in phosgene-induced ALI with Ad/NLRP3-shRNA pretreatment. TUNEL staining indicated decreased pyroptosis in Psg-Ad/NLRP3-shRNA rats. Decreased mRNA and protein levels of NLRP3 and caspase-1 (all P < 0.05), but not ASC (P > 0.05), were found in Psg-Ad/NLRP3-shRNA rats. Immunohistochemistry revealed that Ad/NLRP3-shRNA pretreatment inhibited NLRP3 inflammasome activation. Reduced level of pro-inflammatory interleukin (IL)-1ß, IL-18, IL-33, and tumor necrosis factor (TNF)-α (all P < 0.05), but not of anti-inflammatory IL-4 and IL-10 (all P > 0.05), were found in serum and BALF from Ad/NLRP3-shRNA rats. NLRP3 gene silencing exerts beneficial effects on phosgene-induced lung injury by inhibiting NLRP3 inflammasome activation and pro-inflammatory factors, but not anti-inflammatory factors. Disruption of NLRP3 inflammasome activation might be used as a therapeutic modality for the treatment of phosgene-induced ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Inativação Gênica , Terapia Genética/métodos , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosgênio/envenenamento , RNA Interferente Pequeno/administração & dosagem , Lesão Pulmonar Aguda/diagnóstico , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intravenosas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Masculino , Ratos Sprague-Dawley
2.
Zhonghua Bing Li Xue Za Zhi ; 49(10): 1046-1051, 2020 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-32992421

RESUMO

Objective: To investigate the protective effect of dihydromyricetin (DHM) on doxorubicin (DOX)-induced myocardial injury and its mechanism. Methods: Twenty-four healthy male SD rats were divided into 4 groups: control group, DOX group, DOX+DHM100 group and DOX+DHM200 group. Echocardiography was used to measure cardiac function. At the end of the 6th week, the rats were anesthetized and sacrificed, and the pathological changes of the cardiac tissues were observed by HE staining, Masson staining and WGA staining. Cardiomyocyte apoptosis was observed by TUNEL staining, and protein levels of NLRP3, caspase-1, IL-1ß, bax and bcl-2 were detected by Western blot and immunohistochemistry. Results: Compared with the control group, the left ventricular ejection fraction and left ventricular fractional shortening decreased significantly in DOX group, while left ventricular internal dimension at systole and left ventricular internal dimension at diastole increased. In DOX+DHM group, both left ventricular ejection fraction and left ventricular fractional shortening increased, while left ventricular internal dimension at systole and left ventricular internal dimension at diastole decreased (P<0.05). Furthermore, DOX group showed significant myocardial injury histologically, while DOX+DHM group significantly inhibited DOX-induced myocardial injury in rats. Meanwhile, cardiomyocyte hypertrophy was found in the DOX group, while the cardiomyocyte hypertrophy was notably inhibited in the DOX+DHM group. Compared with the control group, the apoptotic rates of cardiomyocytes and the levels of bax/bcl-2 ratio were significantly increased in DOX group, which were significantly alleviated in the DOX+DHM group (P<0.05). In addition, the levels of NLRP3, caspase-1 and IL-1ß were increased as compared with control group, while the levels of the above indicators were remarkably reversed in DOX+DHM group as compared with DOX group (P<0.05). Conclusion: DHM alleviates DOX-induced myocardial injury in rats by inhibiting NLRP3 inflammasome and reducing cardiomyocyte apoptosis.


Assuntos
Inflamassomos , Função Ventricular Esquerda , Animais , Doxorrubicina , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Sprague-Dawley , Volume Sistólico
3.
Int J Mol Sci ; 21(17)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867310

RESUMO

Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1ß, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.


Assuntos
Betacoronavirus/imunologia , Lesões Encefálicas Traumáticas/fisiopatologia , Infecções por Coronavirus/complicações , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/complicações , Biomarcadores/metabolismo , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pandemias , Prognóstico , Piroptose
4.
Medicine (Baltimore) ; 99(35): e21888, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871918

RESUMO

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with considerable genetic predisposition. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) is crucial for the innate immunity and implicated in SLE pathogenesis. Accordingly, we conducted a case-control study to find the association of NLRP3 variations with SLE susceptibility and disease activity.Three single nucleotide polymorphisms of NLRP3 (rs3806268, rs4612666, and rs10754558) were genotyped in 400 SLE patients and 400 healthy controls; the patients were further divided into mild-to-moderate or high disease activity subgroup. Serum cytokines, complements, and autoantibodies were also detected.We found that rs4612666 TT genotype conferred a higher risk of severe disease activity with adjusted odds ratio = 2.08, P = .02 and adjusted odds ratio  = 2.34, P = .01 in the codominant and recessive model, respectively. Nevertheless, there was no association between the 3 single nucleotide polymorphisms of NLRP3 gene and SLE susceptibility. In addition, C4 decreased significantly in rs3806268 GG (P < .001) and rs4612666 TT genotype carriers (P = .03). A higher trend of interleukin-1ß and interleukin-γ release were identified in rs3806268 AA and rs10754558 CC genotype carriers, respectively.NLRP3 polymorphisms are associated with SLE disease activity and hypocomplementemia. Interleukin-1ß and interleukin-γ levels in SLE patients are correlated with NLRP3 variants as well.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C4/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Subunidade gama Comum de Receptores de Interleucina/sangue , Interleucina-1beta/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
5.
PLoS Negl Trop Dis ; 14(9): e0008632, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32976511

RESUMO

There is an urgent need for the development of new, improved vaccine adjuvants against T. spiralis infection. Polysaccharides are effective, safe, and biodegradable as adjuvant. In our study, we first observed the protective efficacy of lentinan as adjuvant against helminth T. spiralis infection. Recombinant T. spiralis Serpin (rTs-Serpin) immunoscreened from a cDNA library of T. spiralis, as a vaccine, protect host against Trichinella infection. The reduction rate of helminth burden of rTs-Serpin+lentinan-immunized mice was significantly increased compared with rTs-Serpin+FCA -immunized mice. rTs-Serpin+lentinan induced IgG1-dominant immune response and higher levels of IFN-γ and IL-4. rTs-Serpin+lentinan displayed a lower reduction rate of parasite burden in NLRP3-/- mice than that in WT mice and lower level of IgG1 than that in WT mice. The level of IL-4, but not IFN-γ, from NLRP3-/- mice immunized by rTs-Serpin+lentinan was significantly lower than that from WT mice, suggesting that NLRP3 is associated with rTs-Serpin+lentinan -triggering Th2 protective immunity against T. spiralis infection. In summary, we revealed that lentinan was a novel adjuvant against T. spiralis infection via NLRP3. NLRP3 therefore represents an important target for adjuvant discovery and the control of T. spiralis infection.


Assuntos
Adjuvantes Imunológicos , Lentinano/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Trichinella spiralis/efeitos dos fármacos , Trichinella spiralis/imunologia , Triquinelose/imunologia , Vacinas/imunologia , Animais , Anticorpos Anti-Helmínticos , Antígenos de Helmintos/genética , Antígenos de Helmintos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunização , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Serpinas/genética , Serpinas/imunologia , Trichinella spiralis/genética , Triquinelose/prevenção & controle
6.
PLoS Biol ; 18(8): e3000807, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760056

RESUMO

Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens.


Assuntos
Células da Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Proteínas de Ligação a DNA/genética , Inflamassomos/efeitos da radiação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Ligação a Fosfato/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proteínas de Ligação a DNA/deficiência , Feminino , Fêmur/citologia , Fêmur/metabolismo , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteínas de Ligação a Fosfato/deficiência , Piroptose/genética , Piroptose/efeitos da radiação , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Baço/efeitos da radiação , Transplante Isogênico , Irradiação Corporal Total , Raios X
7.
J Biol Chem ; 295(41): 14040-14052, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32763970

RESUMO

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.


Assuntos
Caspase 8/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Células Cultivadas , Coronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/veterinária , Citocinas/metabolismo , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Necroptose , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo
8.
J Stroke Cerebrovasc Dis ; 29(9): 105037, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807449

RESUMO

BACKGROUND: Cerebral ischemia/reperfusion (I/R) injury after ischemic stroke is usually accompanied with the activation of inflammasome which seriously impairs neurological function. MiR-139 has been reported to be associated with inflammatory regulation in multiple diseases. However, its effect and mechanism on inflammation regulation after cerebral I/R injury are still poorly understood. METHODS: An in vitro model of cerebral I/R injury was constructed with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. TargetScan bioinformatics analysis and dual luciferase reporter assay were utilized to confirm the targeted relationship between miR-139 and c-Jun. Cell pyroptosis was verified by flow cytometry and Caspase-1 Detection Kit. qRT-PCR assay was performed to detect the expression levels of miR-139, c-Jun, NLRP3 and ASC. Western blotting was applied to measure the protein levels of c-Jun and pyroptosis-related markers NLRP3, ASC, caspase-1, GSDMDNterm. The ELISA assay was applied to measure the release of IL-1ß, IL-18 and LDH. RESULTS: MiR-139 was significantly downregulated whereas c-Jun was obviously upregulated after OGD/R treatment. TargetScan analysis predicted that c-Jun was a potential target of miR-139, which was verified by the dual-luciferase reporter assay. Also, overexpression of miR-139 repressed c-Jun expression. Furthermore, miR-139 inhibited OGD/R-induced cell pyroptosis and the upregulation of NLRP3, caspase-1, ASC, GSDMDNterm, and the release of IL-1ß, IL-18 and LDH, while miR-139 inhibition exerted the opposite effects. However, overexpression of c-Jun aggravated OGD/R-induced nerve injury and partly abolished the neuroprotective effect of miR-139. CONCLUSION: Upregulation of miR-139 exerted neuroprotection against OGD/R-induced nerve injury by negatively regulating c-Jun/NLRP3 inflammasome signaling. This study offered insights for providing potential therapeutic targets for treating cerebral I/R injury.


Assuntos
Inflamassomos/metabolismo , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Piroptose , Traumatismo por Reperfusão/prevenção & controle , Caspase 1/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Glucose/deficiência , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , L-Lactato Desidrogenase/metabolismo , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neurônios/patologia , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
9.
PLoS Pathog ; 16(8): e1008327, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32853276

RESUMO

Host resistance to Toxoplasma gondii relies on CD8 T cell IFNγ responses, which if modulated by the host or parasite could influence chronic infection and parasite transmission between hosts. Since host-parasite interactions that govern this response are not fully elucidated, we investigated requirements for eliciting naïve CD8 T cell IFNγ responses to a vacuolar resident antigen of T. gondii, TGD057. Naïve TGD057 antigen-specific CD8 T cells (T57) were isolated from transnuclear mice and responded to parasite-infected bone marrow-derived macrophages (BMDMs) in an antigen-dependent manner, first by producing IL-2 and then IFNγ. T57 IFNγ responses to TGD057 were independent of the parasite's protein export machinery ASP5 and MYR1. Instead, host immunity pathways downstream of the regulatory Immunity-Related GTPases (IRG), including partial dependence on Guanylate-Binding Proteins, are required. Multiple T. gondii ROP5 isoforms and allele types, including 'avirulent' ROP5A from clade A and D parasite strains, were able to suppress CD8 T cell IFNγ responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFNγ differentiation occurs independently of parasite virulence or any known IRG-ROP5 interaction. Consistent with this, removal of ROP5 is not enough to elicit maximal CD8 T cell IFNγ production to parasite-infected cells. Instead, macrophage expression of the pathogen sensors, NLRP3 and to a large extent NLRP1, were absolute requirements. Other members of the conventional inflammasome cascade are only partially required, as revealed by decreased but not abrogated T57 IFNγ responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFNγ production was only partially reduced in the absence of IL-12, IL-18 or IL-1R signaling. In summary, T. gondii effectors and host machinery that modulate parasitophorous vacuolar membranes, as well as NLR-dependent but inflammasome-independent pathways, determine the full commitment of CD8 T cells IFNγ responses to a vacuolar antigen.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Inflamassomos/imunologia , Interferon gama/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Protozoários/metabolismo , Transdução de Sinais , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Animais , Linfócitos T CD8-Positivos/parasitologia , Feminino , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Protozoários/genética , Toxoplasmose Animal/parasitologia , Vacúolos/imunologia , Vacúolos/metabolismo , Vacúolos/parasitologia , Virulência/imunologia
10.
Sci Total Environ ; 745: 141049, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-32758727

RESUMO

Hyperandrogenism is the main cause of infertility as a result of polycystic ovary syndrome (PCOS). Long-term and continuous exposure to hyperandrogen can cause follicular developmental disorders. Ovarian granulosa cells (GCs) are critical in shaping the follicular development. To clarify how excessive androgen suppresses folliculogenesis and ovulation, we constructed PCOS mice by implantation of a 35-d testosterone (T) continuous-release pellet. Ovarian toll-like receptor 4 (TLR4) expression and serum IL-6 and IL-1ß levels were dramatically increased in T-treated mice. In addition, the expression of NLRP3 inflammasome in the ovary of T-treated mice suggests that pyroptosis may play an essential role in follicular dysfunction. Lipopolysaccharide (LPS) has been extensively studied for activating cells by binding to TLR4. In this study, we demonstrated that LPS-induced inflammation leads to activation of the NLRP3 inflammasome with consequent impacts on follicular dysfunction. Herein we showed that LPS treatment upregulated the expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and androgen receptor (AR), while suppressed follicle stimulating hormone receptor (FSHR) expression in vitro. Moreover, we overexpressed NLRP3 using nigericin or lentiviral particles in GCs. The protein and mRNA levels of pyroptotic factors were highly enhanced with NLRP3 overexpression. As expected, the expression of Cyp19α1, Cyp11α1, 3ß-HSD and FSHR at both the protein and mRNA levels was also markedly increased with excessive NLRP3. After inhibiting NLRP3, dihydrotestosterone (DHT)-treated GCs demonstrated markedly decreased NLRP3, the inflammasome adapter protein ASC, C-terminal fragment of gasdermin D (GSDMD-C), AR and Cyp19α1 at the protein level. Furthermore, with NLRP3 overexpression, the expression of fibrotic factors in ovarian cells was dramatically increased, such as TGF-ß, CTGF, α-SMA, ß-catenin, collagen I and collagen IV. These findings suggest that hyperandrogen stimulates chronic low-grade inflammation in the ovary to activate the NLRP3 inflammasome, further inducing a series of pathologies including ovarian GC pyroptotic death, follicular dysfunction and ovarian interstitial cell fibrosis.


Assuntos
Inflamassomos , Piroptose , Animais , Feminino , Fibrose , Interleucina-1beta , Lipopolissacarídeos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
11.
PLoS One ; 15(8): e0237752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817626

RESUMO

Pseudomonas aeruginosa remains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals. P. aeruginosa infection triggers host immune response and often provokes potent inflammatory mediators, which do not necessarily eradicate the causative pathogen. On the other hand, it causes severe airway damage and eventually decreased lung function. Such unfavorable outcomes of inflammatory injury have necessitated the development of novel effective agents that can combat with P. aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulating P. aeruginosa-induced inflammation, with particular emphasized on the interleukin-1ß (IL-1ß). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1ß in macrophages infected by live P. aeruginosa PAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1ß during P. aeruginosa infection, pre- or even post-infection. In addition, quercetin strongly suppressed MAPK signaling pathway by inhibiting phosphorylation of the p38 MAPK and JNK2, and molecular docking study supported well with this observation. Moreover, quercetin reduced the NLRP3 expression and inhibited the P. aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1ß. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1ß production is mediated by suppressing the initial priming step and by inhibiting the NLRP3 inflammasome activation. Taken together, our findings demonstrated the promising regulatory activity of quercetin against IL-1ß production in P. aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment of P. aeruginosa-induced inflammation.


Assuntos
Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Infecções por Pseudomonas/tratamento farmacológico , Quercetina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Transdução de Sinais/efeitos dos fármacos
12.
J Stroke Cerebrovasc Dis ; 29(8): 104874, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689633

RESUMO

INTRODUCTION: Previous studies have reported the involvement of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the inflammatory activation and pathophysiology of Ischemic Stroke (IS). Variations in genes encoding the constituent proteins of NLRP3 inflammasome can alter the risk of IS. OBJECTIVE: We investigated the role of the NLRP3 inflammasome in the pathogenesis of IS by establishing associations between combined polymorphisms of caspase recruitment domain-containing protein 8 (CARD8) rs2043211 and NLRP3 rs10754558 and the susceptibility to IS in a Chinese population. METHODS: Single nucleotide polymorphisms (SNPs) in CARD8 rs2043211 and NLRP3 rs10754558 were analyzed using TaqMan SNP genotyping assays in patients with IS (n=234) and healthy controls (n=115). Logistic regression analysis was carried out to evaluate potential interactions between CARD8 and NLRP3. RESULTS: Compared with healthy controls, there were no significant differences in the minor allele frequency (MAF) and the genotype frequency of NLRP3 rs10754558 or CARD8 rs2043211 in patients with IS(P>0.05). After stratification by gender, there was an increased risk for IS in men carrying heterozygous CARD8 rs2043211 when a co-dominant genetic model was applied (P=0.021, OR=3.83[1.22-12.03]). Logistic regression analysis indicated that men carrying both CARD8 rs2043211 AT and NLRP3 rs10754558 CG had a significantly higher risk of IS (P=0.046, OR=7.116[1.033-49.044]). CONCLUSIONS: Nucleotide variations in the genes encoding NLRP3 inflammasome proteins may be important to IS, and men carrying CARD8 rs2043211 and NLRP3 rs10754558, both heterozygous, confer a higher risk of IS.


Assuntos
Isquemia Encefálica/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Interação Gene-Ambiente , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etnologia
13.
J Cancer Res Ther ; 16(3): 405-409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719244

RESUMO

Activation of inflammasomes has a decisive role in host defense mechanism against pathogens and other intracellular risk factors, but recently, it has been revealed that they play a significant role in the pathogenesis of several diseases, including cancer. Nod-like receptor protein 3 (NLRP3) inflammasome, the best-studied inflammasome, has contrasting roles in cancer development and progressions. In head-and-neck cancers, the upregulated level of NLRP3 promotes tumor progression. The main objective of this review is to provide current knowledge on the involvement of NLRP3 inflammasome in head-and-neck cancers. Deeper understanding of the biology of this dynamic protein complex provides new scope for the development of more effective anticancer therapies.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Imunidade Inata , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais
14.
Leukemia ; 34(7): 1726-1729, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483300

RESUMO

The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine "storm," which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?


Assuntos
Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Células-Tronco Hematopoéticas/virologia , Inflamassomos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/prevenção & controle , Lesão Renal Aguda/virologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Furanos/farmacologia , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamassomos/genética , Miocardite/epidemiologia , Miocardite/imunologia , Miocardite/prevenção & controle , Miocardite/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , Piroptose/genética , Piroptose/imunologia , Fatores de Risco , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
15.
J Neurosci ; 40(28): 5480-5494, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32499379

RESUMO

Neuroinflammation can be caused by various insults to the brain and represents an important pathologic hallmark of neurodegenerative diseases including Alzheimer's disease (AD). Infection-triggered acute systemic inflammation is able to induce neuroinflammation and may negatively affect neuronal morphology, synaptic plasticity, and cognitive function. In contrast to acute effects, persisting consequences for the brain on systemic immune stimulation remain largely unexplored. Here, we report an age-dependent vulnerability of wild-type (WT) mice of either sex toward a systemic immune stimulation by Salmonella typhimurium lipopolysaccharide (LPS). Decreased neuronal complexity three months after peripheral immune stimulation is accompanied by impairment in long-term potentiation (LTP) and spatial learning. Aged APP/PS1 mice reveal an increased sensitivity also to LPS of Escherichia coli, which had no effect in WT mice. We further report that these effects are mediated by NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, since the genetic ablation and pharmacological inhibition using the NLRP3 inhibitor MCC950 rescue the morphological and electrophysiological phenotype.SIGNIFICANCE STATEMENT Acute peripheral immune stimulation has been shown to have both positive and negative effects on Aß deposition. Improvements or worsening may be possible in acute inflammation. However, there is still no evidence of effects longer than a month after stimulation. The data are pointing to an important role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome for mediating the long-term consequences of systemic immune stimulation, which in addition turns out to be age dependent.


Assuntos
Encéfalo/imunologia , Inflamassomos/metabolismo , Inflamação/metabolismo , Potenciação de Longa Duração/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Aprendizagem Espacial/fisiologia , Fatores Etários , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Aprendizagem Espacial/efeitos dos fármacos
16.
Obesity (Silver Spring) ; 28(7): 1270-1282, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32538511

RESUMO

OBJECTIVE: This study aimed to investigate whether the NLRP3 inflammasome in Kupffer cells (KCs) can be activated in response to high glucose (HG) and to evaluate its influence on hepatic insulin sensitivity. METHODS: Primary KCs and hepatocytes were isolated from mice, and lipid accumulation, glucose output, and insulin sensitivity of hepatocytes were investigated after culturing either alone or with KCs exposed to HG. The influence of HG-induced NLRP3 inflammasome activation in KCs on insulin sensitivity of hepatocytes was examined. Treatment with gadolinium trichloride caused KC depletion, and, subsequently, a streptozotocin-induced hyperglycemic mouse model was used to confirm the influence of KCs on hepatic insulin sensitivity. RESULTS: Hepatocytes cocultured with KCs showed enhanced lipid accumulation, glucose output, and impaired insulin sensitivity when exposed to HG. Enhanced NLRP3 inflammasome activation was also evident in both hepatocytes and KCs. Moreover, KCs that were pretreated with caspase-1 inhibitor, NLRP3 inhibitor, and NLRP3 small interfering RNA corrected coculture-induced aberrances in insulin action and NLRP3 inflammasome activation in hepatocytes. KC coculture also increased interleukin-1ß (IL-1ß)-mediated nuclear factor-κB (NF-κB) activation in hepatocytes. In hyperglycemic mice, KC depletion inhibited NLRP3 inflammasome activation and improved hepatic insulin sensitivity. CONCLUSIONS: NLRP3 inflammasome activation impaired insulin sensitivity through KC-derived IL-1ß-mediated NF-κB activation in hepatocytes exposed to HG.


Assuntos
Glucose/farmacologia , Inflamassomos/fisiologia , Resistência à Insulina , Macrófagos do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Resistência à Insulina/genética , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
17.
Trends Parasitol ; 36(6): 498-501, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32359871

RESUMO

Epigenetic manipulation of host cells by intracellular pathogens has become increasingly evident. Lecoeur et al. show us how Leishmania amazonensis inhibits macrophage inflammasomes by modifying histone H3 activation marks on NF-κB-associated gene promoters that increase the expression of inhibitors and downmodulates activators of this pathway.


Assuntos
Leishmania , Epigênese Genética , Histonas/metabolismo , Inflamassomos/metabolismo , Leishmania/metabolismo , Macrófagos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
18.
Sci Rep ; 10(1): 7823, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385413

RESUMO

This study investigates the role of NLRP3 inflammasome and its main effector Caspase-1 in inflammation and alveolar bone resorption associated with periodontitis. Heat-killed Aggregatibacter actinomycetemcomitans (Aa) was injected 3x/week (4 weeks) into gingival tissues of wild-type (WT), Nlrp3-KO and Caspase1-KO mice. Bone resorption was measured by µCT and osteoclast number was determined by tartrate-resistant acid phosphatase (TRAP) staining. Inflammation was assessed histologically (H/E staining and immunofluorescence of CD45 and Ly6G). In vitro studies determined the influence of Nlrp3 and Caspase-1 in Rankl-induced osteoclast differentiation and activity and on LPS-induced expression of inflammation-associated genes. Bone resorption was significantly reduced in Casp1-KO but not in Nlrp3-KO mice. Casp1-KO mice had increased in osteoclast numbers, whereas the inflammatory infiltrate or on gene expression were similar to those of WT and Nlrp3-KO mice. Strikingly, osteoclasts differentiated from Nlrp3-deficient macrophages had increased resorbing activity in vitro. LPS-induced expression of Il-10, Il-12 and Tnf-α was significantly reduced in Nlrp3- and Casp1-deficient macrophages. As an inceptive study, these results suggest that Nlrp3 inflammasome does not play a significant role in inflammation and bone resorption in vivo and that Caspase-1 has a pro-resorptive role in experimental periodontal disease.


Assuntos
Perda do Osso Alveolar/genética , Caspase 1/genética , Inflamação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Periodontite/genética , Aggregatibacter actinomycetemcomitans , Perda do Osso Alveolar/microbiologia , Perda do Osso Alveolar/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Gengiva/crescimento & desenvolvimento , Gengiva/microbiologia , Humanos , Inflamação/microbiologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-12/genética , Camundongos , Camundongos Knockout , Osteoclastos/microbiologia , Osteoclastos/patologia , Periodontite/microbiologia , Periodontite/patologia , Ligante RANK/genética , Fator de Necrose Tumoral alfa/genética
19.
Int J Mol Sci ; 21(9)2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32365944

RESUMO

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1ß in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3-/- mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.


Assuntos
Quimiocina CXCL10/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Vírus da SARS/metabolismo , Proteínas Virais/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Quimiocina CXCL10/genética , Modelos Animais de Doenças , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pneumonia/patologia , Pneumonia/virologia , Regiões Promotoras Genéticas , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Regulação para Cima , Proteínas Virais/química , Proteínas Virais/genética
20.
Life Sci ; 254: 117796, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417375

RESUMO

AIMS: To explore the possible mechanism that microRNA-223 regulates the spinal cord injury as well as the posttranscriptional control of genes after spinal injury. MATERIALS AND METHODS: Rats contusion spinal cord injury model and microglia model were established and examined by pathological test and the inflammatory cytokines levels were evaluated by RT-PCR. Then microRNA-223 was overexpressed in spinal cord to see the impact on rats with spinal cord injury. The overexpression of microRNA-223 in microglia stimulated by LPS was used to assess the inflammation. Then bioinformatic method combined with luciferase reporter genes were used to detect the target gene of microRNA-223. Then NLRP3, one of the target genes of microRNA-223 were regulated to see the impact on microglia as well as spinal injury rats. KEY FINDINGS: It showed that microRNA-223 increased after acute spinal injury. However, the suppression of microRNA-223 aggravated the spinal injury as well as the inflammation while the over-expression of microRNA-223 alleviated the spinal injury to some extent, decreased the inflammation and improved nervous system function. In vitro, it was found that the over-expression of microRNA-223 in microglia suppressed inflammation induced by LPS and vice versa. NLRP3 was found the target of microRNA-223. The up-regulation of NLRP3 could diminish the effects of microRNA-223 and aggravated inflammation in microglia. SIGNIFICANCE: The over-expression of microRNA-223 alleviated the inflammation and improved neuron function. NLRP3 was the downstream target of microRNA-223, the overexpression of which led to severe inflammation in microglia.


Assuntos
Inflamação/prevenção & controle , MicroRNAs/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Citocinas/metabolismo , Inflamação/complicações , Lipopolissacarídeos , MicroRNAs/biossíntese , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Cultura Primária de Células , Ratos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
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