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1.
Mol Med ; 30(1): 102, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39009982

RESUMO

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.


Assuntos
Ferroptose , Necroptose , Humanos , Células THP-1 , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Piperazinas/farmacologia , Acrilamidas , Sulfonamidas , Proteínas de Ligação a RNA , Complexo de Proteínas Formadoras de Poros Nucleares
2.
CNS Neurosci Ther ; 30(7): e14835, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39004783

RESUMO

AIMS: Necroptosis is one of programmed death that may aggravate spinal cord injury (SCI). We aimed to investigate the effect and mechanism of exendin-4 (EX-4) on the recovery of motor function and necroptosis after SCI. METHODS: The SD rats with left hemisection in the T10 spinal cord as SCI model were used. The behavior tests were measured within 4 weeks. The effects of EX-4 on necroptosis-associated proteins and autophagy flux were explored. In addition, the SHSY5Y cell model was introduced to explore the direct effect of EX-4 on neurons. The effect of lysosome was explored using mTOR activator and AO staining. RESULTS: EX-4 could improve motor function and limb strength, promote the recovery of autophagy flux, and accelerate the degradation of necroptosis-related protein at 3 d after injury in rats. EX-4 reduced lysosome membrane permeability, promoted the recovery of lysosome function and autophagy flux, and accelerated the degradation of necroptosis-related proteins by inhibiting the phosphorylation level of mTOR in the SHSY5Y cell model. CONCLUSION: Our results demonstrated that EX-4 may improve motor function after SCI via inhibiting mTOR phosphorylation level and accelerating the degradation of necroptosis-related proteins in neurons. Our findings may provide new therapeutic targets for clinical treatment after SCI.


Assuntos
Autofagia , Exenatida , Necroptose , Neurônios , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Animais , Autofagia/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Ratos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Exenatida/farmacologia , Exenatida/uso terapêutico , Necroptose/efeitos dos fármacos , Humanos , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Fármacos Neuroprotetores/farmacologia , Masculino
3.
Circ Arrhythm Electrophysiol ; 17(7): e012452, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39012929

RESUMO

BACKGROUND: Aging is one of the most potent risk determinants for the onset of atrial fibrillation (AF). Sirts (sirtuins) have been implicated in the pathogenesis of cardiovascular disease, and their expression declines with aging. However, whether Sirts involved in age-related AF and its underlying mechanisms remain unknown. The present study aims to explore the role of Sirts in age-related AF and delineate the underlying molecular mechanisms. METHODS: Sirt1 levels in the atria of both elderly individuals and aging rats were evaluated using quantitative real-time polymerase chain reaction and Western blot analysis. Mice were engineered to specifically knockout Sirt1 in the atria and right ventricle (Sirt1mef2c/mef2c). Various techniques, such as echocardiography, atrial electrophysiology, and protein acetylation modification omics were employed. Additionally, coimmunoprecipitation was utilized to substantiate the interaction between Sirt1 and RIPK1 (receptor-interacting protein kinase 1). RESULTS: We discerned that among the diverse subtypes of sirtuin proteins, only Sirt1 expression was significantly diminished in the atria of elderly people and aged rats. The Sirt1mef2c/mef2c mice exhibited an enlarged atrial diameter and heightened vulnerability to AF. Acetylated proteomics and cell experiments identified that Sirt1 deficiency activated atrial necroptosis through increasing RIPK1 acetylation and subsequent pseudokinase MLKL (mixed lineage kinase domain-like protein) phosphorylation. Consistently, necroptotic inhibitor necrosulfonamide mitigated atrial necroptosis and diminished both the atrial diameter and AF susceptibility of Sirt1mef2c/mef2c mice. Resveratrol prevented age-related AF in rats by activating atrial Sirt1 and inhibiting necroptosis. CONCLUSIONS: Our findings first demonstrated that Sirt1 exerts significant efficacy in countering age-related AF by impeding atrial necroptosis through regulation of RIPK1 acetylation, highlighting that the activation of Sirt1 or the inhibition of necroptosis could potentially serve as a therapeutic strategy for age-related AF.


Assuntos
Fibrilação Atrial , Modelos Animais de Doenças , Átrios do Coração , Camundongos Knockout , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Sirtuína 1/genética , Acetilação , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/prevenção & controle , Fibrilação Atrial/patologia , Masculino , Humanos , Ratos , Envelhecimento/metabolismo , Envelhecimento/patologia , Camundongos , Ratos Sprague-Dawley , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais , Fatores Etários , Idoso , Camundongos Endogâmicos C57BL , Feminino
4.
Nat Commun ; 15(1): 6043, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39025845

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.


Assuntos
Antígeno CD47 , Carcinoma Ductal Pancreático , Transição Epitelial-Mesenquimal , Armadilhas Extracelulares , Neoplasias Hepáticas , Macrófagos , Necroptose , Neoplasias Pancreáticas , Proteínas Quinases , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/genética , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Linhagem Celular Tumoral , Antígeno CD47/metabolismo , Antígeno CD47/genética , Proteínas Quinases/metabolismo , Armadilhas Extracelulares/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/genética , Masculino , Transdução de Sinais , Feminino , Acrilamidas , Sulfonamidas
5.
Respir Res ; 25(1): 271, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987753

RESUMO

BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear. METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma. RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway. CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.


Assuntos
Asma , Camundongos Knockout , Necroptose , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Animais , Asma/metabolismo , Asma/patologia , Necroptose/fisiologia , Humanos , Camundongos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Masculino , Feminino , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Camundongos Endogâmicos C57BL , Proteínas Quinases/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Ovalbumina/toxicidade
6.
Sci Rep ; 14(1): 16032, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992075

RESUMO

This study explores the application of the RIP3-caspase3-assay in heterogeneous spheroid cultures to analyze cell death pathways, emphasizing the nuanced roles of apoptosis and necroptosis. By employing directly conjugated monoclonal antibodies, we provide detailed insights into the complex mechanisms of cell death. Our findings demonstrate the assay's capability to differentiate between RIP1-independent apoptosis, necroptosis, and RIP1-dependent apoptosis, marking a significant advancement in organoid research. Additionally, we investigate the effects of TNFα on isolated intestinal epithelial cells, revealing a concentration-dependent response and an adaptive or threshold reaction to TNFα-induced stress. The results indicate a preference for RIP1-independent cell death pathways upon TNFα stimulation, with a notable increase in apoptosis and a secondary role of necroptosis. Our research underscores the importance of the RIP3-caspase3-assay in understanding cell death mechanisms in organoid cultures, offering valuable insights for disease modeling and the development of targeted therapies. The assay's adaptability and robustness in spheroid cultures enhances its potential as a tool in personalized medicine and translational research.


Assuntos
Apoptose , Caspase 3 , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores , Esferoides Celulares , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Humanos , Esferoides Celulares/metabolismo , Esferoides Celulares/efeitos dos fármacos , Caspase 3/metabolismo , Apoptose/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Morte Celular/efeitos dos fármacos , Organoides/metabolismo , Organoides/citologia
7.
Sci Immunol ; 9(97): eadn0178, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38996010

RESUMO

Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)-expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA-binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude-greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.


Assuntos
COVID-19 , Necroptose , Piroptose , Proteínas de Ligação a RNA , Mucosa Respiratória , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/patologia , Necroptose/imunologia , Animais , Mucosa Respiratória/virologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Camundongos , Morte Celular/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Apoptose/imunologia
8.
Sci Immunol ; 9(97): eadp8170, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38996011

RESUMO

Upon SARS-CoV-2 infection, infected cells undergo necroptosis, whereas delayed apoptosis and pyroptosis occur in uninfected, bystander cells, thus providing a plausible explanation for the extensive injury among myriad uninfected cells.


Assuntos
COVID-19 , Necroptose , Piroptose , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/patologia , SARS-CoV-2/imunologia , Piroptose/imunologia , Necroptose/imunologia , Apoptose/imunologia , Morte Celular/imunologia , Animais
9.
Mol Biol Cell ; 35(8): ar108, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38959101

RESUMO

Our recent work has uncovered a novel function of HSPA8 as an amyloidase, capable of dismantling the RHIM-containing protein fibrils to suppress necroptosis. However, the impact of HSPA8 inhibitors on cancer regression via necroptosis remains unexplored. In this study, we conducted a comprehensive investigation to assess the potential of HSPA8 inhibitors in enhancing necroptosis both in vitro and in vivo. Our findings indicate that pharmacologic inhibition of HSPA8, achieved either through VER (VER-155008) targeting the nucleotide binding domain or pifithrin-µ targeting the substrate binding domain of HSPA8, significantly potentiates necroptosis induced by diverse treatments in cellular assays. These inhibitors effectively disrupt the binding of HSPA8 to the RHIM protein, impeding its regulatory function on RHIM amyloid formation. Importantly, HSPA8 inhibitors significantly enhanced cancer cell sensitivity to microtubule-targeting agents (MTAs) in vitro, while reversing chemoresistance and facilitating tumor regression by augmenting necroptosis in vivo. Our findings suggest a promising therapeutic approach to cancer through necroptosis modulation via HSPA8 targeting, particularly in combination with MTA drugs for enhanced treatment efficacy.


Assuntos
Proteínas de Choque Térmico HSC70 , Necroptose , Neoplasias , Necroptose/efeitos dos fármacos , Humanos , Animais , Linhagem Celular Tumoral , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas de Choque Térmico HSC70/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nucleosídeos de Purina
11.
Int J Mol Med ; 54(3)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38963054

RESUMO

PANoptosis, a complex form of proinflammatory programmed cell death, including apoptosis, pyroptosis and necroptosis, has been an emerging concept in recent years that has been widely reported in cancer, infectious diseases and neurological disorders. Cardiovascular diseases (CVDs) are an important global health problem, posing a serious threat to individuals' lives. An increasing body of research shows that inflammation has a pivotal role in CVDs, which provides an important theoretical basis for PANoptosis to promote the progression of CVDs. To date, only sporadic studies on PANoptosis in CVDs have been reported and its role in the field of CVDs has not been fully explored. Elucidating the various modes of cardiomyocyte death, the specific molecular mechanisms and the links among the various modes of death under various stressful stimuli is of notable clinical significance for a deeper understanding of the pathophysiology of CVDs. The present review summarizes the molecular mechanisms of apoptosis, pyroptosis, necroptosis and PANoptosis and their prospects in the field of CVDs.


Assuntos
Doenças Cardiovasculares , Necroptose , Piroptose , Humanos , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/metabolismo , Animais , Apoptose/fisiologia , Morte Celular Regulada , Inflamação/patologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo
12.
13.
J Nanobiotechnology ; 22(1): 355, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38902678

RESUMO

BACKGROUND: Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse. RESULTS: The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection. CONCLUSIONS: These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Desoxicitidina , Gencitabina , Hidrogéis , Neoplasias Pulmonares , Necroptose , Animais , Camundongos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Hidrogéis/química , Humanos , Necroptose/efeitos dos fármacos , Recidiva Local de Neoplasia , Linhagem Celular Tumoral , Imunoterapia/métodos , Terapia Fototérmica/métodos , Infecção dos Ferimentos/prevenção & controle , Infecção dos Ferimentos/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos
14.
J Exp Clin Cancer Res ; 43(1): 168, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877579

RESUMO

PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements of pyroptosis, apoptosis, and necroptosis. PANoptosis is governed by a newly discovered cytoplasmic multimeric protein complex known as the PANoptosome. Unlike each of these PCD types individually, PANoptosis is still in the early stages of research and warrants further exploration of its specific regulatory mechanisms and primary targets. In this review, we provide a brief overview of the conceptual framework and molecular components of PANoptosis. In addition, we highlight recent advances in the understanding of the molecular mechanisms and therapeutic applications of PANoptosis. By elucidating the complex crosstalk between pyroptosis, apoptosis and necroptosis and summarizing the functional consequences of PANoptosis with a special focus on the tumor immune microenvironment, this review aims to provide a theoretical basis for the potential application of PANoptosis in cancer therapy.


Assuntos
Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Morte Celular , Necroptose , Microambiente Tumoral/imunologia , Animais , Piroptose , Apoptose
15.
Acta Neuropathol ; 147(1): 96, 2024 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-38852117

RESUMO

Although apoptosis, pyroptosis, and ferroptosis have been implicated in AD, none fully explains the extensive neuronal loss observed in AD brains. Recent evidence shows that necroptosis is abundant in AD, that necroptosis is closely linked to the appearance of Tau pathology, and that necroptosis markers accumulate in granulovacuolar neurodegeneration vesicles (GVD). We review here the neuron-specific activation of the granulovacuolar mediated neuronal-necroptosis pathway, the potential AD-relevant triggers upstream of this pathway, and the interaction of the necrosome with the endo-lysosomal pathway, possibly providing links to Tau pathology. In addition, we underscore the therapeutic potential of inhibiting necroptosis in neurodegenerative diseases such as AD, as this presents a novel avenue for drug development targeting neuronal loss to preserve cognitive abilities. Such an approach seems particularly relevant when combined with amyloid-lowering drugs.


Assuntos
Doença de Alzheimer , Necroptose , Humanos , Necroptose/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Animais , Neurônios/patologia , Neurônios/metabolismo , Degeneração Neural/patologia , Degeneração Neural/metabolismo
16.
Front Immunol ; 15: 1401626, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38868779

RESUMO

Zinc finger Asp-His-His-Cys motif-containing (zDHHC) proteins, known for their palmitoyltransferase (PAT) activity, play crucial roles in diverse cellular processes, including immune regulation. However, their non-palmitoyltransferase immunomodulatory functions and involvement in teleost immune responses remain underexplored. In this study, we systematically characterized the zDHHC family in the large yellow croaker (Larimichthys crocea), identifying 22 members. Phylogenetic analysis unveiled that each of the 22 LczDHHCs formed distinct clusters with their orthologues from other teleost species. Furthermore, all LczDHHCs exhibited a highly conserved DHHC domain, as confirmed by tertiary structure prediction. Notably, LczDHHC23 exhibited the most pronounced upregulation following Pseudomonas plecoglossicida (P. plecoglossicida) infection of macrophage/monocyte cells (MO/MΦ). Silencing LczDHHC23 led to heightened pro-inflammatory cytokine expression and diminished anti-inflammatory cytokine levels in MO/MΦ during infection, indicating its anti-inflammatory role. Functionally, LczDHHC23 facilitated M2-type macrophage polarization, as evidenced by a significant skewing of MO/MΦ towards the pro-inflammatory M1 phenotype upon LczDHHC23 knockdown, along with the inhibition of MO/MΦ necroptosis induced by P. plecoglossicida infection. These findings highlight the non-PAT immunomodulatory function of LczDHHC23 in teleost immune regulation, broadening our understanding of zDHHC proteins in host-pathogen interactions, suggesting LczDHHC23 as a potential therapeutic target for immune modulation in aquatic species.


Assuntos
Proteínas de Peixes , Macrófagos , Necroptose , Perciformes , Animais , Perciformes/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas de Peixes/metabolismo , Necroptose/imunologia , Filogenia , Ativação de Macrófagos/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Aciltransferases/genética , Aciltransferases/imunologia , Pseudomonas/fisiologia , Citocinas/metabolismo
17.
Cell Death Dis ; 15(6): 403, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858387

RESUMO

Necroptosis is an inflammatory form of cell suicide that critically depends on the kinase activity of Receptor Interacting Protein Kinase 3 (RIPK3). Previous studies showed that immunization with necroptotic cells conferred protection against subsequent tumor challenge. Since RIPK3 can also promote apoptosis and NF-κB-dependent inflammation, it remains difficult to determine the contribution of necroptosis-associated release of damage-associated molecular patterns (DAMPs) in anti-tumor immunity. Here, we describe a system that allows us to selectively induce RIPK3-dependent necroptosis or apoptosis with minimal NF-κB-dependent inflammatory cytokine expression. In a syngeneic tumor challenge model, immunization with necroptotic cells conferred superior protection against subsequent tumor challenge. Surprisingly, this protective effect required CD4+ T cells rather than CD8+ T cells and is dependent on host type I interferon signaling. Our results provide evidence that death-dependent type I interferon production following necroptosis is sufficient to elicit protective anti-tumor immunity.


Assuntos
Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores , Necroptose/imunologia , Animais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Interferon Tipo I/metabolismo , Linfócitos T CD8-Positivos/imunologia , Transdução de Sinais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Humanos , NF-kappa B/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos
18.
Nat Commun ; 15(1): 4920, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858353

RESUMO

The differentiation of the stroma is a hallmark event during postnatal uterine development. However, the spatiotemporal changes that occur during this process and the underlying regulatory mechanisms remain elusive. Here, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution and characterized two distinct stromal subpopulations, inner and outer stroma. Furthermore, single-cell RNA sequencing revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing H4K20me1, led to a reduced proportion of the inner stroma due to massive cell death, thus impeding uterine development. By combining RNA sequencing and epigenetic profiling of H4K20me1, we demonstrated that PR-SET7-H4K20me1 either directly repressed the transcription of interferon stimulated genes or indirectly restricted the interferon response via silencing endogenous retroviruses. Declined H4K20me1 level caused viral mimicry responses and ZBP1-mediated apoptosis and necroptosis in stromal cells. Collectively, our study provides insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7.


Assuntos
Epigênese Genética , Histona-Lisina N-Metiltransferase , Células Estromais , Útero , Feminino , Animais , Útero/metabolismo , Células Estromais/metabolismo , Camundongos , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Interferons/metabolismo , Interferons/genética , Retrovirus Endógenos/genética , Apoptose/genética , Camundongos Endogâmicos C57BL , Morte Celular/genética , Necroptose/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Histonas/metabolismo , Análise de Célula Única , Camundongos Knockout , Diferenciação Celular/genética
20.
Cell Death Differ ; 31(7): 938-953, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38849574

RESUMO

Z-DNA binding protein 1 (ZBP1) has important functions in anti-viral immunity and in the regulation of inflammatory responses. ZBP1 induces necroptosis by directly engaging and activating RIPK3, however, the mechanisms by which ZBP1 induces inflammation and in particular the role of RIPK1 and the contribution of cell death-independent signaling remain elusive. Here we show that ZBP1 causes skin inflammation by inducing RIPK3-mediated necroptosis and RIPK1-caspase-8-mediated apoptosis in keratinocytes. ZBP1 induced TNFR1-independent skin inflammation in mice with epidermis-specific ablation of FADD by triggering keratinocyte necroptosis. Moreover, transgenic expression of C-terminally truncated constitutively active ZBP1 (ZBP1ca) in mouse epidermis caused skin inflammation that was only partially inhibited by abrogation of RIPK3-MLKL-dependent necroptosis and fully prevented by combined deficiency in MLKL and caspase-8. Importantly, ZBP1ca induced caspase-8-mediated skin inflammation by RHIM-dependent but kinase activity-independent RIPK1 signaling. Furthermore, ZBP1ca-induced inflammatory cytokine production in the skin was completely prevented by combined inhibition of apoptosis and necroptosis arguing against a cell death-independent pro-inflammatory function of ZBP1. Collectively, these results showed that ZBP1 induces inflammation by activating necroptosis and RIPK1 kinase activity-independent apoptosis.


Assuntos
Apoptose , Caspase 8 , Inflamação , Queratinócitos , Necroptose , Proteínas de Ligação a RNA , Proteína Serina-Treonina Quinases de Interação com Receptores , Animais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Camundongos , Caspase 8/metabolismo , Inflamação/patologia , Inflamação/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Queratinócitos/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Transdução de Sinais , Humanos , Proteínas Quinases/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
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