RESUMO
Respiratory viruses, including SARS-CoV-2, influenza, parainfluenza, rhinovirus, and respiratory syncytial virus (RSV), are pathogens responsible for lower respiratory tract infections, particularly in vulnerable populations such as children and the elderly. Upon infection, these viruses are recognized by pattern recognition receptors, leading to the activation of inflammasomes, which are essential for mediating inflammatory responses. This review discusses the mechanisms by which these RNA respiratory viruses activate inflammasomes, emphasizing the roles of various signaling pathways and components involved in this process. Additionally, we highlight the specific interactions between viral proteins and inflammasome sensors, elucidating how these viruses manipulate the host immune response to facilitate infection. Understanding the dynamics of inflammasome activation in response to respiratory viruses provides critical insights for developing immunomodulatory therapeutic strategies aimed at mitigating inflammation and improving outcomes in respiratory tract infections.
Assuntos
Inflamassomos , Vírus de RNA , Infecções Respiratórias , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Infecções Respiratórias/terapia , Animais , Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Transdução de Sinais , Infecções por Vírus de RNA/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , COVID-19/imunologia , COVID-19/virologia , COVID-19/terapia , Interações Hospedeiro-Patógeno/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologiaRESUMO
The complement system plays a crucial role in various pathophysiological conditions, including snake envenomation. In this study, we investigated the effects of Bitis arietans venom on the complement system using an ex vivo human whole blood model. Our findings demonstrate that B. arietans venom was able to activate the complement system, leading to a significant increase in the production of anaphylatoxins (C3a/C3a-desArg, C5a/C5a-desArg) and the soluble Terminal Complement Complex (sTCC). Inhibition of the C3 component by Cp40, a C3-C3b inhibitor, resulted in the reduction of C3a/C3a-desArg, C5a/C5a-desArg, and sTCC levels to baseline in venom-stimulated samples. Furthermore, treatment with Cp40 promoted a substantial decrease in the production of pro-inflammatory mediators, such as Prostaglandin E2 (PGE2), IL-8/CXCL8, MCP-1/CCL2, and MIG/CXCL9. To further elucidate the molecular mechanisms, we utilized the THP-1 cell line differentiated into M0 macrophages. Incubation of these macrophages with human plasma, from the human whole blood treated with B. arietans venom, resulted in the expression of the NLRP3 inflammasome and the production of IL-8 and IL-1ß. Importantly, Cp40 was able to diminish the production of these cytokines, as well as the levels of ASC and caspase-1 proteins. In conclusion, our results indicate that the inhibition of the complement by Cp40 at C3/C3b level can modulate the inflammatory response and inflammasome activation induced by B. arietans venom. These findings suggest that complement inhibition may be a promising therapeutic approach for managing the inflammatory complications associated with this snake envenomation.
Assuntos
Complemento C3 , Inflamassomos , Humanos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Animais , Complemento C3/metabolismo , Complemento C3/antagonistas & inibidores , Células THP-1 , Venenos de Víboras , Viperidae , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/imunologia , Ativação do Complemento/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Citocinas/metabolismo , Anafilatoxinas/metabolismo , Inativadores do Complemento/farmacologia , Viperinae , Serpentes PeçonhentasRESUMO
PURPOSE OF REVIEW: This review aims to comprehensively examine the immune response following traumatic brain injury (TBI) and how its disruption can impact healing and recovery. RECENT FINDINGS: The immune response is now considered a key element in the pathophysiology of TBI, with consequences far beyond the acute phase after injury. A delicate equilibrium is crucial for a healthy recovery. When this equilibrium is disrupted, chronic inflammation and immune imbalance can lead to detrimental effects on survival and disability. Globally, traumatic brain injury (TBI) imposes a substantial burden in terms of both years of life lost and years lived with disability. Although its epidemiology exhibits dynamic trends over time and across regions, TBI disproportionally affects the younger populations, posing psychosocial and financial challenge for communities and families. Following the initial trauma, the primary injury is succeeded by an inflammatory response, primarily orchestrated by the innate immune system. The inflammasome plays a pivotal role during this stage, catalyzing both programmed cell death pathways and the up-regulation of inflammatory cytokines and transcription factors. These events trigger the activation and differentiation of microglia, thereby intensifying the inflammatory response to a systemic level and facilitating the migration of immune cells and edema. This inflammatory response, initially originated in the brain, is monitored by our autonomic nervous system. Through the vagus nerve and adrenergic and cholinergic receptors in various peripheral lymphoid organs and immune cells, bidirectional communication and regulation between the immune and nervous systems is established.
Assuntos
Lesões Encefálicas Traumáticas , Humanos , Lesões Encefálicas Traumáticas/imunologia , Animais , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamassomos/imunologia , Inflamassomos/metabolismoRESUMO
Increased energy intake from carbohydrates has been associated with major cardiovascular outcomes. Mice fed a highly-refined carbohydrate (HC) diet develop cardiac hypertrophy and inflammation. During cardiac injury, NLRP3 inflammasome is activated which results in a local inflammatory response. In this study, we hypothesized that a nom-hypoglycemic dose of glibenclamide may reverses sugar diet-induced cardiac damage by NRLP3 inflammasome inhibition. Mice were fed the HC diet for eight weeks and divided into a group treated with glibenclamide (20 mg/kg, gavage) and another with vehicle for four weeks. Afterward, hearts were excised for morphometric analysis and ex vivo function determination. NLRP3 inflammasome activation was investigated by western blotting and in situ fluorescent detection of reactive oxygen species (ROS) and active caspase-1. The HC diet promotes heart hypertrophy and collagen deposition, which were reverted by glibenclamide without ameliorating HC diet-induced insulin resistance. Changes in cardiac performance were observed in vivo by invasive catheterization and in Langendorff-perfused hearts due to the HC diet, which were prevented by glibenclamide. Hearts from HC diet mice had increased levels of NLRP3 and cleaved IL-1ß. Glibenclamide reversed ROS production and caspase-1 activity induced by HC diet. These findings suggest glibenclamide's cardioprotective effects on heart damage caused by the HC diet are related to its inhibitory action on the NLRP3 inflammasome.
Assuntos
Glibureto , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Glibureto/farmacologia , Inflamassomos/metabolismo , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Caspase 1/metabolismo , Interleucina-1beta/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Açúcares da Dieta/efeitos adversosRESUMO
Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.
Assuntos
Autofagia , Inflamassomos , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Autofagia/efeitos dos fármacos , Inflamassomos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Feminino , Masculino , Benzotiazóis/farmacologia , Pessoa de Meia-Idade , Sorafenibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Idoso , Compostos de FenilureiaRESUMO
NLRP1, the first identified inflammasome-forming sensor, is thought to be involved in cancer, yet its definite function in lung adenocarcinoma (LUAD) remains unclear. Herein, we explored the expression and function of NLRP1 in LUAD. Decreased NLRP1 expression was identified in LUAD, which was associated with a poor prognosis. Overexpression of NLRP1 inhibited tumor growth in vitro and in vivo. Mechanically, this effect was observed regardless of inflammasome activation. Further studies revealed that overexpression of NLRP1 downregulated the phosphorylation of DRP1 and promoted mitochondrial fusion, which was mediated by inhibition of NF-κB activity. NF-κB agonist could neutralize the effect of NLRP1 on mitochondrial dynamics. In addition, LUAD sensitivity to cisplatin was enhanced by decreased mitochondrial fission resulting from up-regulated NLRP1. In conclusion, our findings demonstrated an unexpected role of NLRP1 in LUAD by modulating mitochondrial activities, which provides strong evidence for its potential in LUAD treatment.
Assuntos
Adenocarcinoma de Pulmão , Inflamassomos , Neoplasias Pulmonares , Mitocôndrias , Proteínas NLR , Humanos , Inflamassomos/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Proteínas NLR/metabolismo , Animais , Mitocôndrias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/fisiologia , Camundongos , Masculino , Proliferação de Células/efeitos dos fármacos , FemininoRESUMO
The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On the one hand, TMEM176B promotes antigen cross-presentation to CD8+ T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, it inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. We speculated that formulating BayK8644 in PEGylated chitosan nanoparticles (NP-PEG-BayK8644) should slowly release the compound and by that mean avoid cross-presentation inhibition (which happens with a fast 30 min kinetics) while still triggering inflammasome activation. Chitosan nanocarriers were successfully obtained, exhibiting a particle size within the range of 200 nm; they had a high positive surface charge and a 99 % encapsulation efficiency. In in vitro studies, NP-PEG-BayK8644 did not inhibit antigen cross-presentation by DCs, unlike the free compound. The NP-PEG-BayK8644 activated the inflammasome in a Tmem176b-dependent manner in DCs. We administered either empty (eNP-PEG) or NP-PEG-BayK8644 to mice with established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and improved mice survival compared to both eNP-PEG and free BayK8644 in melanoma and lymphoma models. This effect was associated with enhanced inflammasome activation by DCs in the tumor-draining lymph node and infiltration of the tumor by CD8+ T cells. Thus, encapsulation of BayK8644 in chitosan NPs improves the anti-tumoral properties of the compound by avoiding inhibition of antigen cross-presentation.
Assuntos
Imunidade Adaptativa , Quitosana , Células Dendríticas , Imunidade Inata , Nanopartículas , Quitosana/química , Quitosana/farmacologia , Animais , Nanopartículas/química , Camundongos , Imunidade Adaptativa/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Proteínas de Membrana/imunologia , Inflamassomos/metabolismo , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/tratamento farmacológico , Polietilenoglicóis/química , Polietilenoglicóis/farmacologiaRESUMO
The search for bioactive compounds in natural products holds promise for discovering new pharmacologically active molecules. This study explores the anti-inflammatory potential of açaí (Euterpe oleracea Mart.) constituents against the NLRP3 inflammasome using high-throughput molecular modeling techniques. Utilizing methods such as molecular docking, molecular dynamics simulation, binding free energy calculations (MM/GBSA), and in silico toxicology, we compared açaí compounds with known NLRP3 inhibitors, MCC950 and NP3-146 (RM5). The docking studies revealed significant interactions between açaí constituents and the NLRP3 protein, while molecular dynamics simulations indicated structural stabilization. MM/GBSA calculations demonstrated favorable binding energies for catechin, apigenin, and epicatechin, although slightly lower than those of MCC950 and RM5. Importantly, in silico toxicology predicted lower toxicity for açaí compounds compared to synthetic inhibitors. These findings suggest that açaí-derived compounds are promising candidates for developing new anti-inflammatory therapies targeting the NLRP3 inflammasome, combining efficacy with a superior safety profile. Future research should include in vitro and in vivo validation to confirm the therapeutic potential and safety of these natural products. This study underscores the value of computational approaches in accelerating natural product-based drug discovery and highlights the pharmacological promise of Amazonian biodiversity.
Assuntos
Anti-Inflamatórios , Inflamassomos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Euterpe/química , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analyzed in two Brazilian patients with typical UBA1 mutations, and compared with healthy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Inflamassomos , Interleucina-18 , Leucócitos Mononucleares , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas NLR , Neutrófilos , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18/sangue , Interleucina-18/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Proteínas NLR/genética , Feminino , Masculino , Neutrófilos/imunologia , Caspase 1/genética , Idoso , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Enzimas Ativadoras de Ubiquitina/genética , Febre/imunologia , Mutação , Brasil , Proteínas de NeoplasiasRESUMO
BACKGROUND: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated. METHODS: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed. RESULTS: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1ß, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone. CONCLUSION: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.
Assuntos
Catecóis , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Dieta Hiperlipídica , Inflamassomos , Metformina , MicroRNAs , Animais , Masculino , Ratos , Catecóis/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Quimioterapia Combinada , Álcoois Graxos/farmacologia , Hipoglicemiantes/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Metformina/farmacologia , Metformina/administração & dosagem , MicroRNAs/metabolismo , MicroRNAs/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Receptor 4 Toll-Like/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: The absence of melanoma 2 (AIM2) protein triggers the activation of the inflammasome cascade. It is unclear whether AIM2 plays a role in hepatocellular carcinoma (HCC) and radiofrequency ablation (RFA), which uses radiofrequency waves to treat tumors. In this study, we investigated if RFA could induce pyroptosis, also called cell inflammatory necrosis, in HCC through AIM2-inflammasome signaling in vivo and in vitro. MATERIALS AND METHODS: BALB/c nude mice were used to generate HepG2 or SMMC-7721 cell-derived tumor xenografts. HCC cells with knockdown or overexpression of AIM2 were created using short hairpin RNA (shRNA) and expression vector transfection, respectively, for functional and mechanistic studies. Downstream effects were examined using flow cytometry, qRT-PCR, ELISAs, and other molecular assays. RESULTS: RFA significantly suppressed tumor growth in HCC cell xenografts. Flow cytometry analysis revealed that RFA could induce pyroptosis. Furthermore, AIM2, NLRP3, caspase-1, γ-H2AX, and DNA-PKc had significantly greater expression levels in liver tissues from mice treated with RFA compared with those of the controls. Additionally, interleukin (IL)-1ß and IL-18 expression levels were significantly higher in the HCC cell-derived xenograft mice treated with RFA compared with those without RFA. Notably, a significantly greater effect was achieved in the RFA complete ablation group versus the partial ablation group. Knockdown or overexpression of AIM2 in HCC cells demonstrated that AIM2 exerted a role in RFA-induced pyroptosis. CONCLUSIONS: RFA can suppress HCC tumor growth by inducing pyroptosis via AIM2. Therefore, therapeutically intervening with AIM2-mediated inflammasome signaling may help improve RFA treatment outcomes for HCC patients.
Assuntos
Carcinoma Hepatocelular , Proteínas de Ligação a DNA , Inflamassomos , Interleucina-1beta , Neoplasias Hepáticas , Piroptose , Ablação por Radiofrequência , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirurgia , Caspase 1/metabolismo , Caspase 1/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células Hep G2 , Histonas/metabolismo , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-18/genética , Interleucina-1beta/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais , Carga TumoralRESUMO
The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3-/-) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3-/- mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3-/- macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3-/- mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3-/- mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15.
Assuntos
Imunidade Inata , Macrófagos Peritoneais , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Taenia , Teníase , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Camundongos , Teníase/imunologia , Taenia/imunologia , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Células Cultivadas , Inflamassomos/metabolismo , Inflamassomos/imunologiaRESUMO
COVID-19 has affected more than half a billion people worldwide, with more than 6.3 million deaths, but the pathophysiological mechanisms involved in lethal cases and the host determinants that determine the different clinical outcomes are still unclear. In this study, we assessed lung autopsies of 47 COVID-19 patients and examined the inflammatory profiles, viral loads, and inflammasome activation. Additionally, we correlated these factors with the patient's clinical and histopathological conditions. Robust inflammasome activation was detected in the lungs of lethal cases of SARS-CoV-2. Experiments conducted on transgenic mice expressing hACE2 and infected with SARS-CoV-2 showed that Nlrp3-/- mice were protected from disease development and lethality compared to Nlrp3+/+ littermate mice, supporting the involvement of this inflammasome in disease exacerbation. An analysis of gene expression allowed for the classification of COVID-19 patients into two different clusters. Cluster 1 died with higher viral loads and exhibited a reduced inflammatory profile than Cluster 2. Illness time, mechanical ventilation time, pulmonary fibrosis, respiratory functions, histopathological status, thrombosis, viral loads, and inflammasome activation significantly differed between the two clusters. Our data demonstrated two distinct profiles in lethal cases of COVID-19, thus indicating that the balance of viral replication and inflammasome-mediated pulmonary inflammation led to different clinical outcomes. We provide important information to understand clinical variations in severe COVID-19, a process that is critical for decisions between immune-mediated or antiviral-mediated therapies for the treatment of critical cases of COVID-19.
Assuntos
COVID-19 , Pulmão , SARS-CoV-2 , Carga Viral , Replicação Viral , COVID-19/virologia , COVID-19/mortalidade , COVID-19/imunologia , COVID-19/patologia , Animais , Humanos , Camundongos , Feminino , Masculino , Pulmão/virologia , Pulmão/patologia , Pulmão/imunologia , Pessoa de Meia-Idade , Inflamassomos/imunologia , Inflamassomos/metabolismo , Idoso , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Transgênicos , Pneumonia/virologia , Pneumonia/mortalidade , Pneumonia/imunologia , Pneumonia/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Camundongos Knockout , AdultoRESUMO
INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.
Assuntos
Modelos Animais de Doenças , Inflamassomos , Terapia de Alvo Molecular , Transtornos do Humor , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/fisiopatologia , Camundongos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologiaRESUMO
Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP]5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1ß, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.
Assuntos
Hipotireoidismo , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Animais , Gravidez , Feminino , Ratos , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inflamassomos/metabolismo , Modelos Animais de Doenças , Placenta/metabolismo , Placenta/efeitos dos fármacos , Placentação/efeitos dos fármacos , Antioxidantes/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Manganês , Metaloporfirinas/farmacologia , Chaperona BiP do Retículo EndoplasmáticoRESUMO
Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.
Assuntos
Proteínas de Transporte , Dieta Hiperlipídica , Glucose , Resistência à Insulina , Músculo Esquelético , Proteína 3 que Contém Domínio de Pirina da Família NLR , Obesidade , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Tiorredoxinas , Animais , Masculino , Camundongos , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Dieta Hiperlipídica/efeitos adversos , Furanos/farmacologia , Glucose/metabolismo , Indenos/farmacologia , Inflamassomos/metabolismo , Insulina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/metabolismo , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas , Tiorredoxinas/metabolismo , Tiorredoxinas/genéticaRESUMO
Legionella species are Gram-negative intracellular bacteria that evolved in soil and freshwater environments, where they infect and replicate within various unicellular protozoa. The primary virulence factor of Legionella is the expression of a type IV secretion system (T4SS), which contributes to the translocation of effector proteins that subvert biological processes of the host cells. Because of its evolution in unicellular organisms, T4SS effector proteins are not adapted to subvert specific mammalian signaling pathways and immunity. Consequently, Legionella pneumophila has emerged as an interesting infection model for investigating immune responses against pathogenic bacteria in multicellular organisms. This review highlights recent advances in our understanding of mammalian innate immunity derived from studies involving L. pneumophila. This includes recent insights into inflammasome-mediated mechanisms restricting bacterial replication in macrophages, mechanisms inducing cell death in response to infection, induction of effector-triggered immunity, activation of specific pulmonary cell types in mammalian lungs, and the protective role of recruiting monocyte-derived cells to infected lungs.
Assuntos
Imunidade Inata , Legionella pneumophila , Doença dos Legionários , Legionella pneumophila/imunologia , Legionella pneumophila/patogenicidade , Humanos , Animais , Doença dos Legionários/imunologia , Doença dos Legionários/microbiologia , Fagócitos/imunologia , Fagócitos/microbiologia , Sistemas de Secreção Tipo IV/imunologia , Sistemas de Secreção Tipo IV/genética , Sistemas de Secreção Tipo IV/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Monócitos/imunologia , Monócitos/microbiologia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Interações Hospedeiro-Patógeno/imunologiaRESUMO
25-hydroxycholesterol (25-HC) plays a role in the regulation of cell survival and immunity. However, the effect of 25-HC on myocardial ischemia/reperfusion (MI/R) injury remains unknown. Our present study aimed to investigate whether 25-HC aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. The overlapping differentially expressed genes (DEGs) in MI/R were identified from the GSE775, GSE45818, GSE58486, and GSE46395 datasets in Gene Expression Omnibus (GEO) database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the database of Annotation, Visualization and Integration Discovery (DAVID). The protein-protein interaction (PPI) network of the overlapping DEGs was established using the Search Tool for the Retrieval of Interacting Genes (STRING) database. These bioinformatics analyses indicated that cholesterol 25-hydroxylase (CH25H) was one of the crucial genes in MI/R injury. The oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was established to simulate MI/R injury. Western blot and RT-qPCR analysis demonstrated that CH25H was significantly upregulated in OGD/R-stimulated H9C2 cardiomyocytes. Moreover, knockdown of CH25H inhibited the OGD/R-induced pyroptosis and nod-like receptor protein 3 (NLRP3) inflammasome activation, as demonstrated by cell counting kit-8 (CCK8), lactate dehydrogenase (LDH), RT-qPCR, and western blotting assays. Conversely, 25-HC, which is synthesized by CH25H, promoted activation of NLRP3 inflammasome in OGD/R-stimulated H9C2 cardiomyocytes. In addition, the NLRP3 inhibitor BAY11-7082 attenuated 25-HC-induced H9C2 cell injury and pyroptosis under OGD/R condition. In conclusion, 25-HC could aggravate OGD/R-induced pyroptosis through promoting activation of NLRP3 inflammasome in H9C2 cells.
Assuntos
Glucose , Hidroxicolesteróis , Inflamassomos , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Animais , Ratos , Western Blotting , Glucose/metabolismo , Hidroxicolesteróis/metabolismo , Hidroxicolesteróis/farmacologia , Inflamassomos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxigênio/metabolismo , Piroptose/fisiologiaRESUMO
Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus, and chronic skin colonization by Staphylococcus aureus. To understand the inflammatory status in AD, we investigated the inflammasome complex, that activates ASC (Apoptosis-associated speck-like protein containing a CARD), caspase-1 and GSDMD (gasdermin-D), and production of IL-1ß and IL-18. We aimed to evaluate the expression of the inflammasome pathway in the skin of adults with AD. Thirty patients with moderate to severe AD and 20 healthy controls were enrolled in the study. We performed the analysis of the inflammasome components NLRP1, NLRP3, AIM-2, IL-1ß, IL-18, Caspase-1, ASC, GSDMD, and CD68 expression (macrophage marker) by immunohistochemistry and immunofluorescence. The main findings included increased expression of NLRP3, NLRP1 and AIM-2 at dermal level of severe AD; augmented IL-18 and IL-1ß expression at epidermis of moderate and severe patients, and in the dermis of severe AD; augmented expression of ASC, caspase-1 and GSDMD in both epidermis and dermis of moderate and severe AD. We detected positive correlation between caspase-1, GSDMD and IL-1ß (epidermis) and caspase-1 (dermis) and AD severity; NLRP3, AIM-2 and IL-1ß, and NLRP3 with IL-18 in the epidermis; ASC, GSDMD and IL-1ß, and NLRP3, AIM-2, caspase-1, and IL-18 in the dermis. We also evidenced the presence of CD68+ macrophages secreting GSDMD, ASC and IL-1ß in moderate and severe AD. Cutaneous macrophages, early detected in moderate AD, have its role in the disease inflammatory mechanisms. Our study indicates a canonical activation pathway of inflammasomes, reinforced by the chronic status of inflammation in AD. The analysis of the inflammasome complex evidenced an imbalance in its regulation, with increased expression of the evaluated components, which is remarkably in severe AD, emphasizing its relevance as potential disease biomarkers and targets for immunomodulatory interventions.
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Caspase 1 , Dermatite Atópica , Inflamassomos , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Estudos de Casos e Controles , Caspase 1/metabolismo , Molécula CD68 , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Proteínas de Ligação a DNA , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Gasderminas , Inflamassomos/metabolismo , Inflamassomos/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Índice de Gravidade de Doença , Pele/patologia , Pele/imunologia , Pele/metabolismoRESUMO
Ulcerative colitis (UC) is a difficult intestinal disease characterized by inflammation, and its mechanism is complex and diverse. Angiopoietin-like protein 2 (ANGPT2) plays an important regulatory role in inflammatory diseases. However, the role of ANGPT2 in UC has not been reported so far. After exploring the expression level of ANGPT2 in serum of UC patients, the reaction mechanism of ANGPT2 was investigated in dextran sodium sulfate (DSS)-induced UC mice. After ANGPT2 expression was suppressed, the clinical symptoms and pathological changes of UC mice were detected. Colonic infiltration, oxidative stress, and colonic mucosal barrier in UC mice were evaluated utilizing immunohistochemistry, immunofluorescence, and related kits. Finally, western blot was applied for the estimation of mTOR signaling pathway and NLRP3 inflammasome-related proteins. ANGPT2 silencing improved clinical symptoms and pathological changes, alleviated colonic inflammatory infiltration and oxidative stress, and maintained the colonic mucosal barrier in DSS-induced UC mice. The regulatory effect of ANGPT2 on UC disease might occur by regulating the mTOR signaling pathway and thus affecting autophagy-mediated NLRP3 inflammasome inactivation. ANGPT2 silencing alleviated UC by regulating autophagy-mediated NLRP3 inflammasome inactivation via the mTOR signaling pathway.