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1.
Annu Rev Immunol ; 42(1): 615-645, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38941608

RESUMO

The COVID-19 pandemic was caused by the recently emerged ß-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.


Assuntos
COVID-19 , Imunidade Inata , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Infecções por Coronavirus/prevenção & controle , Evasão da Resposta Imune
2.
Cell ; 184(1): 149-168.e17, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33278357

RESUMO

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.


Assuntos
COVID-19/imunologia , COVID-19/patologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Interferon gama/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Morte Celular , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Inflamação/patologia , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Células THP-1
3.
Nat Immunol ; 22(5): 550-559, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33707781

RESUMO

The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1ß or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.


Assuntos
Inflamassomos/metabolismo , Doenças Metabólicas/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias/metabolismo , Animais , Citocinas/metabolismo , Humanos , Inflamassomos/imunologia , Doenças Metabólicas/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias/imunologia , Transdução de Sinais , Microambiente Tumoral
4.
Cell ; 173(4): 920-933.e13, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29576451

RESUMO

Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Inflamassomos/metabolismo , Fatores Reguladores de Interferon/metabolismo , Proteína Inibidora de Apoptose Neuronal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Citocinas/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Flagelina/metabolismo , Fatores Reguladores de Interferon/antagonistas & inibidores , Fatores Reguladores de Interferon/genética , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Inibidora de Apoptose Neuronal/genética , Regiões Promotoras Genéticas , Ligação Proteica , Pseudomonas aeruginosa/patogenicidade , Piroptose , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Salmonella typhimurium/patogenicidade , Transcrição Gênica
5.
Nature ; 573(7775): 590-594, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31511697

RESUMO

The cellular stress response has a vital role in regulating homeostasis by modulating cell survival and death. Stress granules are cytoplasmic compartments that enable cells to survive various stressors. Defects in the assembly and disassembly of stress granules are linked to neurodegenerative diseases, aberrant antiviral responses and cancer1-5. Inflammasomes are multi-protein heteromeric complexes that sense molecular patterns that are associated with damage or intracellular pathogens, and assemble into cytosolic compartments known as ASC specks to facilitate the activation of caspase-1. Activation of inflammasomes induces the secretion of interleukin (IL)-1ß and IL-18 and drives cell fate towards pyroptosis-a form of programmed inflammatory cell death that has major roles in health and disease6-12. Although both stress granules and inflammasomes can be triggered by the sensing of cellular stress, they drive contrasting cell-fate decisions. The crosstalk between stress granules and inflammasomes and how this informs cell fate has not been well-studied. Here we show that the induction of stress granules specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The stress granule protein DDX3X interacts with NLRP3 to drive inflammasome activation. Assembly of stress granules leads to the sequestration of DDX3X, and thereby the inhibition of NLRP3 inflammasome activation. Stress granules and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell-fate decisions under stress conditions. Induction of stress granules or loss of DDX3X in the myeloid compartment leads to a decrease in the production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages use the availability of DDX3X to interpret stress signals and choose between pro-survival stress granules and pyroptotic ASC specks. Together, our data demonstrate the role of DDX3X in driving NLRP3 inflammasome and stress granule assembly, and suggest a rheostat-like mechanistic paradigm for regulating live-or-die cell-fate decisions under stress conditions.


Assuntos
Morte Celular/genética , RNA Helicases DEAD-box/metabolismo , Inflamassomos/genética , Macrófagos/citologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Fisiológico/genética , Animais , Linhagem Celular , Sobrevivência Celular/genética , RNA Helicases DEAD-box/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Células HEK293 , Humanos , Inflamassomos/imunologia , Macrófagos/imunologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
6.
J Biol Chem ; 299(9): 105141, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37557956

RESUMO

The innate immune system provides the first line of defense against pathogens and cellular insults and is activated by pattern recognition receptors sensing pathogen- or damage-associated molecular patterns. This activation can result in inflammation via cytokine release as well as the induction of lytic regulated cell death (RCD). Innate immune signaling can also induce the expression of interferon regulatory factor 1 (IRF1), an important molecule in regulating downstream inflammation and cell death. While IRF1 has been shown to modulate some RCD pathways, a comprehensive evaluation of its role in inflammatory cell death pathways is lacking. Here, we examined the role of IRF1 in cell death during inflammasome and PANoptosome activation using live cell imaging, Western blotting, and ELISA in primary murine macrophages. IRF1 contributed to the induction of ZBP1- (Z-DNA binding protein 1), AIM2- (absent in melanoma-2), RIPK1- (receptor interacting protein kinase 1), and NLRP12 (NOD-like receptor family, pyrin domain-containing 12)-PANoptosome activation and PANoptosis. Furthermore, IRF1 regulated the cell death under conditions where inflammasomes, along with caspase-8 and RIPK3, act as integral components of PANoptosomes to drive PANoptosis. However, it was dispensable for other inflammasomes that form independent of the PANoptosome to drive pyroptosis. Overall, these findings define IRF1 as an upstream regulator of PANoptosis and suggest that modulating the activation of molecules in the IRF1 pathway could be used as a strategy to treat inflammatory and infectious diseases associated with aberrant inflammatory cell death.


Assuntos
Morte Celular , Proteínas de Ligação a DNA , Inflamassomos , Inflamação , Fator Regulador 1 de Interferon , Peptídeos e Proteínas de Sinalização Intracelular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Ligação a RNA , Proteína Serina-Treonina Quinases de Interação com Receptores , Animais , Camundongos , Inflamassomos/metabolismo , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Macrófagos/imunologia
7.
J Biol Chem ; 296: 100579, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33766561

RESUMO

Viruses and hosts have coevolved for millions of years, leading to the development of complex host-pathogen interactions. Influenza A virus (IAV) causes severe pulmonary pathology and is a recurrent threat to human health. Innate immune sensing of IAV triggers a complex chain of host responses. IAV has adapted to evade host defense mechanisms, and the host has coevolved to counteract these evasion strategies. However, the molecular mechanisms governing the balance between host defense and viral immune evasion is poorly understood. Here, we show that the host protein DEAD-box helicase 3 X-linked (DDX3X) is critical to orchestrate a multifaceted antiviral innate response during IAV infection, coordinating the activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, assembly of stress granules, and type I interferon (IFN) responses. DDX3X activated the NLRP3 inflammasome in response to WT IAV, which carries the immune evasive nonstructural protein 1 (NS1). However, in the absence of NS1, DDX3X promoted the formation of stress granules that facilitated efficient activation of type I IFN signaling. Moreover, induction of DDX3X-containing stress granules by external stimuli after IAV infection led to increased type I IFN signaling, suggesting that NS1 actively inhibits stress granule-mediated host responses and DDX3X-mediated NLRP3 activation counteracts this action. Furthermore, the loss of DDX3X expression in myeloid cells caused severe pulmonary pathogenesis and morbidity in IAV-infected mice. Together, our findings show that DDX3X orchestrates alternate modes of innate host defense which are critical to fight against NS1-mediated immune evasion strategies during IAV infection.


Assuntos
RNA Helicases DEAD-box/metabolismo , Imunidade Inata , Inflamassomos/metabolismo , Vírus da Influenza A/fisiologia , Interferon Tipo I/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Vírus da Influenza A/imunologia , Camundongos
8.
Nature ; 540(7634): 583-587, 2016 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-27951586

RESUMO

NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell-derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.

9.
J Biol Chem ; 295(11): 3394-3400, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-31719149

RESUMO

Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1ß and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1ß production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo However, the signaling components upstream of caspase-8 and pro-IL-1ß cleavage in Pstpip2cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain-containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1ß signaling in Pstpip2cmo mice, thereby inducing cmo These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.


Assuntos
Caspase 8/metabolismo , Inflamassomos/metabolismo , Inflamação/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteomielite/patologia , Quinase Syk/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Inflamação/complicações , Inflamação/diagnóstico por imagem , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteomielite/complicações , Osteomielite/diagnóstico por imagem , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais
10.
J Biol Chem ; 295(52): 18276-18283, 2020 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-33109609

RESUMO

Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.


Assuntos
Apoptose , Fungos/patogenicidade , Inflamação/patologia , Necroptose , Piroptose , Proteínas de Ligação a RNA/metabolismo , Animais , Humanos , Inflamassomos , Inflamação/etiologia , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação a RNA/genética
11.
Eur J Immunol ; 49(11): 1998-2011, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31372985

RESUMO

AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1ß (IL-1ß) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.


Assuntos
Infecções Bacterianas/imunologia , Neoplasias Colorretais/imunologia , Proteínas de Ligação a DNA/imunologia , Inflamassomos/imunologia , Dermatopatias/imunologia , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA/genética , DNA/imunologia , Proteínas de Ligação a DNA/genética , Diabetes Mellitus/genética , Diabetes Mellitus/imunologia , Diabetes Mellitus/patologia , Regulação da Expressão Gênica/imunologia , Humanos , Inflamassomos/genética , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Micoses/genética , Micoses/imunologia , Micoses/microbiologia , Piroptose/genética , Piroptose/imunologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Dermatopatias/genética , Dermatopatias/patologia , Viroses/genética , Viroses/imunologia , Viroses/virologia
12.
Phytother Res ; 33(10): 2765-2774, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385371

RESUMO

The purpose of this study was to evaluate the pancreatic beta cell protective and glucose uptake enhancing effect of the water extract of Tinospora cordifolia stem (TCSE) by using rat insulinoma (RIN)-m5F cells and 3 T3-L1 adipocytes. RIN-m5F cells were stimulated with interleukin-1ß and interferon-γ, and the effect of TCSE on insulin secretion and cytokine-induced toxicity was measured by ELISA and MTT assay, respectively. The glucose uptake and protein expression were measured by fluorometry and western blotting. Antidiabetic effect of TCSE was measured using streptozotocin-induced diabetic rats. TCSE dose dependently increased cell viability and insulin secretion in RIN-m5F cells. In addition, TCSE increased both the glucose uptake and glucose transporter 4 translocation in 3 T3-L1 adipocytes via PI3K pathway. Finally, TCSE significantly lowered blood glucose and diet intake and increased body weight in streptozotocin-induced diabetic rats. The level of serum insulin and hepatic glycogen was increased, whereas the level of serum triglyceride, total cholesterol, dipeptidyl peptidase-4, and thiobarbituric acid reactive substances was decreased in TCSE-administered rats. TCSE also increased glucose transporter 4 protein expression in the adipose tissue and liver of TCSE-fed diabetic rats. Our results suggested that TCSE preserved RIN-m5F cells from cytokine-induced toxicity and enhanced glucose uptake in 3 T3-L1 adipocytes, which may regulate glucose metabolism in diabetic rats.


Assuntos
Adipócitos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tinospora , Adipócitos/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Estreptozocina
13.
Am J Pathol ; 187(2): 236-244, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27998728

RESUMO

Mutations in the gene encoding pyrin are associated with autoinflammatory disorder Familial Mediterranean Fever (FMF). A FMF-knock-in mouse strain that expresses chimeric pyrin protein with a V726A mutation (MefvV726A/V726A) was generated to model human FMF. This mouse strain shows an autoinflammatory disorder that is prevented by genetic deletion of IL-1 (IL-1) receptor or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC-mediated cell death leads to the release of IL-1α and IL-1ß, both of which signal through IL-1 receptor. Furthermore, caspase-1 and caspase-8 can interact with ASC to mediate secretion of IL-1 cytokines. The specific IL-1 cytokine instigating development of FMF and the enzymatic caspase involved in its secretion currently are unknown. In this study, we show that the autoinflammation observed in MefvV726A/V726A mice is mediated specifically by IL-1ß and not IL-1α. Furthermore, the disorder is dependent on the caspase-1-ASC axis, whereas caspase-8 is dispensable. Concurrently, aberrant IL-1ß release by MefvV726A/V726A monocytes in response to stimulation with lipopolysaccharide also is dependent on the caspase-1-ASC axis. In conclusion, our studies have uncovered a specific role for caspase-1-mediated IL-1ß release in the manifestation of FMF.


Assuntos
Caspase 1/imunologia , Febre Familiar do Mediterrâneo/imunologia , Interleucina-1beta/imunologia , Animais , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Caspase 8/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Técnicas de Introdução de Genes , Camundongos
14.
Phytother Res ; 31(1): 3-26, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27667670

RESUMO

Nelumbo nucifera, also known as sacred lotus, has primarily been used as food throughout the Asian continent, and its medicinal values have been described in Ayurvedic and Traditional Chinese Medicine. The purpose of this study is to systematically characterize the chemical profiling and pharmacological activities of N. nucifera. Herein, we critically reviewed and analysed the phytochemical and pharmacological reports of N. nucifera. Our search for the keyword 'Nelumbo nucifera pharmacology' in all databases reported in Web of Science yielded 373 results excluding reviews and abstracts in document types. Two hundred and forty-three spectrum natural compounds from different parts of N. nucifera belonging to diverse chemical groups, including alkaloids, flavonoids, glycosides, terpenoids, steroids, fatty acids, proteins, minerals, and vitamins have been reported. In addition, distinct pharmacological activities, mainly against cancer, microbial infection, diabetes, inflammation, atherosclerosis, and obesity, have been associated with crude extracts, fractions, and isolated compounds. This review highlights potential use of neferine, liensinine, isoliensinine, and nuciferine in clinical trials. In depth, mechanism of the potential chemical entities from N. nucifera via structure activity relationship needs to be explored to guarantee the stability and safety for the clinical use. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Medicina Tradicional Chinesa/métodos , Nelumbo/química , Fitoterapia/métodos , Extratos Vegetais/química , Sementes/química , Desenho de Fármacos , Extratos Vegetais/farmacologia
15.
Pak J Pharm Sci ; 30(1): 43-48, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28603111

RESUMO

In this study, we investigated the anti-inflammatory effects and mechanisms of Hizikia fusiformis (HF) extracts in lipopolysaccharide (LPS)-induced RAW 264.7 cells. We extracted HF using solvent and sub-critical water techniques. In results, HF extracts inhibited nitric oxide (NO) production in cell-free and LPS-stimulated RAW 264.7 cells. HF210 (extract prepared with sub critical water at 210oC) was most effective. The HF210 extract dose-dependently inhibited inducible nitric oxide synthase expression (iNOS) and nuclear factor kappa (NF-B) p65 translocation from cytosol to the nucleus. Furthermore, HF210 extract dose-dependently inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), Jun N-terminal kinase (JNK), and signal transducers and activators of transcription (STAT)-1in LPS-induced RAW 264.7 cells. Thus, our results suggest that anti-inflammatory effects of HF210 extract showed a noticeable distinction by regulation of multiple signaling pathways in LPS-induced RAW 264.7 cells.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Alga Marinha/química , Transdução de Sinais/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Animais , Anti-Inflamatórios/isolamento & purificação , Relação Dose-Resposta a Droga , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Células RAW 264.7 , Fator de Transcrição STAT1/metabolismo , Solventes/química , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
J Tradit Chin Med ; 36(1): 71-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26946622

RESUMO

OBJECTIVE: To evaluate the effect of Nelumbo Nucifera leaf water extract (NNLE) on insulinoma (RIN) cells induced by interleukin-1ß (IL-1ß) and interferon-g (IFN-γ), and injured pancreatic ß-cells induced by Streptozotocin (STZ) in rats. METHODS: The anti-oxidative effects of NNLE were assessed using 1,1-diphenyl-2-picryl hydrazyl (DPPH) and nitric oxide (NO) scavenging assays. The inhibitory effect of NNLE on α-glucosidase and DPP (dipeptidyl peptidase)-IV was measured in vitro. Pancreatic ß-cell protective and insulin secretory effects were assessed, using IL-1ß and IFN-γ-induced rat RIN cells. STZ-induced diabetic rats were treated with 50, 100, and 400 mg/kg NNLE for 4 weeks. The effects of NNLE on blood glucose (BG), body weight (BW), and lipid profiles were measured. RESULTS: NNLE inhibited DPPH, NO, α-glucosidase, and DPP-IV which were directly linked to the function of ß-cells. Furthermore, NNLE protected RIN cells from toxicity induced by IL-1ß and IFN-γ, decreased NO production, and increased insulin secretion. NNLE caused a significant reduction in blood glucose, triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), and creatinine in STZ-induced diabetic rats. Furthermore, it significantly decreased BW loss in STZ-induced diabetic rats. CONCLUSION: Our results suggest that NNLE reduced the toxicity in insulinoma cells and increased insulin secretion in pancreatic ß-cells in STZ-induced diabetic rats.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Nelumbo/química , Extratos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/genética , Humanos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Interferon gama/genética , Interleucina-1beta/genética , Masculino , Folhas de Planta/química , Ratos , Ratos Wistar , Estreptozocina/efeitos adversos
17.
J Transl Med ; 13: 62, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25889508

RESUMO

BACKGROUND: Glucose homeostasis is distorted by defects of the PI3K/AKT and AMPK pathways in insulin-sensitive tissues, allowing the accumulation of glucose in the blood. The purpose of this study was to assess the effects and mechanisms by which ethanol extract of Caulerpa lentillifera (CLE) regulates glucose metabolism in C57BL/KsJ-db/db (db/db) mice. METHODS: Mice were administered CLE (250 or 500 mg/kg BW) or rosiglitazone (RSG, 10 mg/kg BW) for 6 weeks. Then, oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) were performed, and blood glucose was measured in db/db mice. Levels of insulin and insulin resistance factors in plasma, glycogen content in the liver, and IRS, PI3K, AKT, and GLUT4 expressions in skeletal muscles were measured in db/db mice. Glucose uptake and insulin signaling molecules were measured in L6 myocytes, using fluorometry and Western blotting. RESULTS: CLE significantly decreased fasting blood glucose, glucose level in OGTT and IPITT, plasma insulin, homeostatic model assessment-insulin resistant (HOMA-IR), TNF-α, IL-6, FFA, TG and TC levels, and hepatic glycogen content in db/db mice. CLE significantly increased the activation of IRS, AKT, PI3K, and GLUT4, which are the key effector molecules of the PI3K/AKT pathway in L6 myocytes and the skeletal muscles of db/db mice. The enhanced glucose uptake by CLE was abolished by treatment with a PI3K inhibitor (LY294002), but not by an AMPK inhibitor (compound C) in L6 myocytes. CLE regulated glucose uptake and homeostasis via the PI3K/AKT pathway in myocytes and db/db mice, respectively. CONCLUSION: Our results suggest that CLE could be a potential candidate for the prevention of diabetes.


Assuntos
Glicemia/metabolismo , Caulerpa/química , Resistência à Insulina , Células Musculares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Adenilato Quinase/metabolismo , Tecido Adiposo/metabolismo , Animais , Peso Corporal , Linhagem Celular , Dieta , Epididimo/metabolismo , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Insulina/sangue , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos
18.
Nat Commun ; 15(1): 1739, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409108

RESUMO

Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients.


Assuntos
Transtornos de Estresse por Calor , Lipopolissacarídeos , Humanos , Gasderminas , Morte Celular , Inflamação/genética , Caspases/genética , Resposta ao Choque Térmico/genética , Piroptose , Apoptose , Fatores de Crescimento Neural , Moléculas de Adesão Celular Neuronais
19.
Transl Res ; 252: 45-52, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36150688

RESUMO

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the world. Inflammation is often an underlying risk factor for developing CRC. Maintaining gut homeostasis and balancing inflammation is therefore critical to prevent CRC development. One key class of molecular complexes that impact gut homeostasis are inflammasomes, cytosolic multiprotein immune complexes that assemble upon sensing various intracellular alterations. Inflammasomes regulate inflammation, cell death, cytokine release, signaling cascades, and other cellular processes. Roles for inflammasomes in colitis and colitis-associated CRC have been shown in multiple animal models. The activation of inflammasomes leads to the release of the bioactive forms of interleukin (IL)-1ß and IL-18, the inflammasome effector cytokines. These cytokines ensure an optimal inflammatory immune response during colitis and colitis-associated CRC. The activation of some inflammasome sensors, including NLRP3, NLRP1, NLRP6, and Pyrin, provides protection from colitis-associated CRC via effector cytokine-dependent mechanisms. Additionally, activation of other inflammasome sensors, such as AIM2, NLRC4, and NAIPs, provides mostly effector cytokine-independent protection. Inflammasomes can also act as integral components of PANoptosomes, which are multifaceted complexes that integrate components from other cell death pathways and regulate a unique form of innate immune inflammatory cell death called PANoptosis. Furthermore, IRF1, a key regulator of some inflammasomes and PANoptosomes, has been implicated in CRC. It is therefore critical to consider the role of inflammasomes in effector cytokine-dependent and -independent protection as well as their role in PANoptosis to modulate CRC for therapeutic targeting. Here, we discuss the mechanisms of inflammasome activation, the functions of inflammasomes in CRC, and current obstacles and future perspectives in inflammasome and CRC research.


Assuntos
Colite , Neoplasias Colorretais , Animais , Inflamassomos/metabolismo , Citocinas/metabolismo , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
20.
Viruses ; 15(11)2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-38005819

RESUMO

Influenza A virus (IAV) continues to pose a significant global health threat, causing severe respiratory infections that result in substantial annual morbidity and mortality. Recent research highlights the pivotal role of innate immunity, cell death, and inflammation in exacerbating the severity of respiratory viral diseases. One key molecule in this process is ZBP1, a well-recognized innate immune sensor for IAV infection. Upon activation, ZBP1 triggers the formation of a PANoptosome complex containing ASC, caspase-8, and RIPK3, among other molecules, leading to inflammatory cell death, PANoptosis, and NLRP3 inflammasome activation for the maturation of IL-1ß and IL-18. However, the role for other molecules in this process requires further evaluation. In this study, we investigated the role of MLKL in regulating IAV-induced cell death and NLRP3 inflammasome activation. Our data indicate IAV induced inflammatory cell death through the ZBP1-PANoptosome, where caspases and RIPKs serve as core components. However, IAV-induced lytic cell death was only partially dependent on RIPK3 at later timepoints and was fully independent of MLKL throughout all timepoints tested. Additionally, NLRP3 inflammasome activation was unaffected in MLKL-deficient cells, establishing that MLKL and MLKL-dependent necroptosis do not act upstream of NLRP3 inflammasome activation, IL-1ß maturation, and lytic cell death during IAV infection.


Assuntos
Vírus da Influenza A , Influenza Humana , Humanos , Apoptose/fisiologia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Vírus da Influenza A/metabolismo , Necroptose , Morte Celular , Proteínas Quinases/metabolismo
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