RESUMEN
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.
Asunto(s)
COVID-19 , Necroptosis , Piroptosis , Proteínas de Unión al ARN , Mucosa Respiratoria , SARS-CoV-2 , Humanos , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/patología , Necroptosis/inmunología , Animales , Mucosa Respiratoria/virología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Ratones , Muerte Celular/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Apoptosis/inmunologíaRESUMEN
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.
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COVID-19 , Necroptosis , Piroptosis , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/patología , SARS-CoV-2/inmunología , Piroptosis/inmunología , Necroptosis/inmunología , Apoptosis/inmunología , Muerte Celular/inmunología , AnimalesRESUMEN
RIPK1 is known as a driver of cell death and inflammation. In this issue of Immunity, Imai et al. and Mannion et al. find that these same processes are also induced by RIPK1 inactivation and highlight the therapeutic potential of RIPK1 elimination.
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Inflamación , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Inflamación/inmunología , Humanos , Animales , Muerte Celular/inmunología , RatonesRESUMEN
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/patología , Animales , Muerte Celular/inmunología , Interacciones Huésped-Patógeno/inmunología , Apoptosis , Inmunidad Innata , Autofagia/inmunología , Transducción de Señal , Macrófagos/inmunología , Macrófagos/microbiologíaRESUMEN
Immunogenic cell death (ICD), which results from insufficient cellular adaptation to specific stressors, occupies a central position in the development of novel anticancer treatments. Several therapeutic strategies to elicit ICD - either as standalone approaches or as means to convert immunologically cold tumours that are insensitive to immunotherapy into hot and immunotherapy-sensitive lesions - are being actively pursued. However, the development of ICD-inducing treatments is hindered by various obstacles. Some of these relate to the intrinsic complexity of cancer cell biology, whereas others arise from the use of conventional therapeutic strategies that were developed according to immune-agnostic principles. Moreover, current discovery platforms for the development of novel ICD inducers suffer from limitations that must be addressed to improve bench-to-bedside translational efforts. An improved appreciation of the conceptual difference between key factors that discriminate distinct forms of cell death will assist the design of clinically viable ICD inducers.
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Muerte Celular Inmunogénica , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Muerte Celular Inmunogénica/efectos de los fármacos , Animales , Inmunoterapia/métodos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular/inmunologíaRESUMEN
Both the innate and adaptive immune systems work together to produce immunity. Cancer immunotherapy is a novel approach to tumor suppression that has arisen in response to the ineffectiveness of traditional treatments like radiation and chemotherapy. On the other hand, immune evasion can diminish immunotherapy's efficacy. There has been a lot of focus in recent years on autophagy and other underlying mechanisms that impact the possibility of cancer immunotherapy. The primary feature of autophagy is the synthesis of autophagosomes, which engulf cytoplasmic components and destroy them by lysosomal degradation. The planned cell death mechanism known as autophagy can have opposite effects on carcinogenesis, either increasing or decreasing it. It is autophagy's job to maintain the balance and proper functioning of immune cells like B cells, T cells, and others. In addition, autophagy controls whether macrophages adopt the immunomodulatory M1 or M2 phenotype. The ability of autophagy to control the innate and adaptive immune systems is noteworthy. Interleukins and chemokines are immunological checkpoint chemicals that autophagy regulates. Reducing antigen presentation to induce immunological tolerance is another mechanism by which autophagy promotes cancer survival. Therefore, targeting autophagy is of importance for enhancing potential of cancer immunotherapy.
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Autofagia , Inmunoterapia , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/patología , Autofagia/inmunología , Autofagia/efectos de los fármacos , Inmunoterapia/métodos , Escape del Tumor , Animales , Inmunidad Adaptativa , Muerte Celular/inmunología , Inmunidad InnataRESUMEN
Innate immunity is not only the first line of host defense against microbial infections but is also crucial for the host responses against a variety of noxious stimuli. Z-DNA binding protein 1 (ZBP1) is a cytosolic nucleic acid sensor that can induce inflammatory cell death in both immune and nonimmune cells upon sensing of incursive virus-derived Z-form nucleic acids and self-nucleic acids via its Zα domain. Mechanistically, aberrantly expressed or activated ZBP1 induced by pathogens or noxious stimuli enables recruitment of TANK binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 to drive type I interferon (IFN-I) responses and activation of nuclear factor kappa B (NF-κB) signaling. Meanwhile, ZBP1 promotes the assembly of ZBP1- and absent in melanoma 2 (AIM2)-PANoptosome, which ultimately triggers PANoptosis through caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis. In response to damaged mitochondrial DNA, ZBP1 can interact with cyclic GMP-AMP synthase to augment IFN-I responses but inhibits toll like receptor 9-mediated inflammatory responses. This review summarizes the structure and expression pattern of ZBP1, discusses its roles in human diseases through immune-dependent (e.g., the production of IFN-I and pro-inflammatory cytokines) and -independent (e.g., the activation of cell death) functions, and highlights the attractive prospect of manipulating ZBP1 as a promising therapeutic target in diseases.
Asunto(s)
Muerte Celular , Inmunidad Innata , Inflamación , Proteínas de Unión al ARN , Humanos , Animales , Inflamación/inmunología , Muerte Celular/inmunología , Proteínas de Unión al ARN/inmunología , Proteínas de Unión al ARN/metabolismo , Transducción de Señal/inmunología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/inmunología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Necroptosis/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , FN-kappa B/metabolismo , FN-kappa B/inmunología , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/inmunología , ApoptosisRESUMEN
Background: Due to the immunosuppressive tumor microenvironment (TME), radiation therapy (RT)-mediated immune response is far from satisfactory. How to improve the efficacy of immunogenic RT by priming strong immunogenic cell death (ICD) is an interesting and urgent challenge. Methods: A polyacrylic acid-coated core-shell UiO@Mn3O4 (denoted as UMP) nanocomposite is constructed for immunogenic RT via multiple strategies. Results: Reshaping the TME via Mn3O4-mediated integration of O2 production, GSH depletion, ROS generation and cell cycle arrest, accompanied by Hf-based UiO-mediated radiation absorption, eventually amplifies UMP-mediated RT to induce intense ICD. With the potent ICD induction and reprogrammed tumor-associated macrophages, this synergetic strategy can promote dendritic cells maturation and CD8+ T cells infiltration, and potentiate anti-tumor immunity against primary, distant, and metastatic tumors. Conclusion: This work is expected to shed light on the immunosuppressive TME-reshaping via multiple strategies to reinforce the immunogenic RT outcome and facilitate the development of effective cancer nanomedicine.
Asunto(s)
Muerte Celular , Nanomedicina , Nanoestructuras , Neoplasias , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Puntos de Control del Ciclo Celular , Muerte Celular/inmunología , Muerte Celular/efectos de la radiación , Línea Celular Tumoral , Células Dendríticas/inmunología , Glutatión/metabolismo , Ratones Endogámicos BALB C , Nanomedicina/métodos , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Metástasis de la Neoplasia/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/radioterapia , Oxígeno/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Microambiente Tumoral , Macrófagos Asociados a Tumores/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7-10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.
Asunto(s)
Linfocitos T CD4-Positivos , Muerte Celular , Inmunoterapia , Inflamación , Neoplasias , Microambiente Tumoral , Humanos , Células Presentadoras de Antígenos/inmunología , Antígeno CD11c/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Muerte Celular/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunidad Innata , Inflamación/inmunología , Interferones/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Microambiente Tumoral/inmunología , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Células Mieloides/inmunología , Células TH1/citología , Células TH1/inmunologíaRESUMEN
Natural products constitute and significantly impact many current anti-cancer medical interventions. A subset of natural products induces injury processes in malignant cells that recruit and activate host immune cells to produce an adaptive anti-cancer immune response, a process known as immunogenic cell death. However, a challenge in the field is to delineate forms of cell death and injury that best promote durable antitumor immunity. Addressing this with a single-cell chemical biology natural product discovery platform, like multiplex activity metabolomics, would be especially valuable in human leukemia, where cancer cells are heterogeneous and may react differently to the same compounds. Herein, a new ten-color, fluorescent cell barcoding-compatible module measuring six immunogenic cell injury signaling readouts are as follows: DNA damage response (γH2AX), apoptosis (cCAS3), necroptosis (p-MLKL), mitosis (p-Histone H3), autophagy (LC3), and the unfolded protein response (p-EIF2α). A proof-of-concept screen was performed to validate functional changes in single cells induced by secondary metabolites with known mechanisms within bacterial extracts. This assay was then applied in multiplexed activity metabolomics to reveal an unexpected mammalian cell injury profile induced by the natural product narbomycin. Finally, the functional consequences of injury pathways on immunogenicity were compared with three canonical assays for immunogenic hallmarks, ATP, HMGB1, and calreticulin, to correlate secondary metabolite-induced cell injury profiles with canonical markers of immunogenic cell death. In total, this work demonstrated a new phenotypic screen for discovery of natural products that modulate injury response pathways that can contribute to cancer immunogenicity.
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Antineoplásicos , Productos Biológicos , Proteína HMGB1 , Metabolómica , Neoplasias , Análisis de la Célula Individual , Adenosina Trifosfato , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Biomarcadores , Calreticulina/metabolismo , Muerte Celular/inmunología , Proteína HMGB1/metabolismo , Histonas/metabolismo , Humanos , Metabolómica/métodos , Neoplasias/inmunologíaRESUMEN
Virus infection of adrenal glands can disrupt secretion of mineralocorticoids, glucocorticoids, and sex hormones from the cortex and catecholamines from the medulla, leading to a constellation of symptoms such as fatigue, dizziness, weight loss, nausea, and muscle and joint pain. Specifically, varicella zoster virus (VZV) can produce bilateral adrenal hemorrhage and adrenal insufficiency during primary infection or following reactivation. However, the mechanisms by which VZV affects the adrenal glands are not well-characterized. Herein, we determined if primary human adrenal cortical cells (HAdCCs) infected with VZV support viral replication and produce a proinflammatory environment. Quantitative PCR showed VZV DNA increasing over time in HAdCCs, yet no cell death was seen at 3 days post-infection by TUNEL staining or Western Blot analysis with PARP and caspase 9 antibodies. Compared to conditioned supernatant from mock-infected cells, supernatant from VZV-infected cells contained significantly elevated IL-6, IL-8, IL-12p70, IL-13, IL-4, and TNF-α. Overall, VZV can productively infect adrenal cortical cells in the absence of cell death, suggesting that these cells may be a potential reservoir for ongoing viral replication and proinflammatory cytokine production, leading to chronic adrenalitis and dysfunction.
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Muerte Celular , Herpes Zóster , Virosis , Corteza Suprarrenal , Muerte Celular/inmunología , Muerte Celular/fisiología , Herpes Zóster/metabolismo , Herpes Zóster/patología , Herpesvirus Humano 3/fisiología , Humanos , Inflamación/metabolismo , Interleucinas/metabolismo , Cultivo Primario de Células , Factor de Necrosis Tumoral alfa/metabolismo , Replicación ViralRESUMEN
Allergic immunity is orchestrated by group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells prominently arrayed at epithelial- and microbial-rich barriers. However, ILC2s and Th2 cells are also present in fibroblast-rich niches within the adventitial layer of larger vessels and similar boundary structures in sterile deep tissues, and it remains unclear whether they undergo dynamic repositioning during immune perturbations. Here, we used thick-section quantitative imaging to show that allergic inflammation drives invasion of lung and liver non-adventitial parenchyma by ILC2s and Th2 cells. However, during concurrent type 1 and type 2 mixed inflammation, IFNγ from broadly distributed type 1 lymphocytes directly blocked both ILC2 parenchymal trafficking and subsequent cell survival. ILC2 and Th2 cell confinement to adventitia limited mortality by the type 1 pathogen Listeria monocytogenes. Our results suggest that the topography of tissue lymphocyte subsets is tightly regulated to promote appropriately timed and balanced immunity.
Asunto(s)
Inflamación/inmunología , Interferón gamma/inmunología , Subgrupos Linfocitarios/inmunología , Células Th2/inmunología , Animales , Muerte Celular/inmunología , Movimiento Celular/inmunología , Hipersensibilidad/inmunología , Inmunidad Innata , Interleucina-33/inmunología , Interleucina-5/metabolismo , Listeria monocytogenes , Listeriosis/inmunología , Listeriosis/mortalidad , Hígado/inmunología , Pulmón/inmunología , Subgrupos Linfocitarios/metabolismo , Lisofosfolípidos/inmunología , Ratones , Tejido Parenquimatoso/inmunología , Esfingosina/análogos & derivados , Esfingosina/inmunología , Células TH1/inmunología , Células Th2/metabolismoRESUMEN
Natural killer (NK) cells are innate cytotoxic lymphocytes that play a key role in cancer immunosurveillance thanks to their ability to recognize and kill cancer cells. NKG2D is an activating receptor that binds to MIC and ULBP molecules typically induced on damaged, transformed or infected cells. The release of NKG2D ligands (NKG2DLs) in the extracellular milieu through protease-mediated cleavage or by extracellular vesicle (EV) secretion allows cancer cells to evade NKG2D-mediated immunosurveillance. In this work, we investigated the immunomodulatory properties of the NKG2D ligand MICA*008 associated to distinct populations of EVs (i.e., small extracellular vesicles [sEVs] and medium size extracellular vesicles [mEVs]). By using as model a human MICA*008-transfected multiple myeloma (MM) cell line, we found that this ligand is present on both vesicle populations. Interestingly, our findings reveal that NKG2D is specifically involved in the uptake of vesicles expressing its cognate ligand. We provide evidence that MICA*008-expressing sEVs and mEVs are able on one hand to activate NK cells but, following prolonged stimulation induce a sustained NKG2D downmodulation leading to impaired NKG2D-mediated functions. Moreover, our findings show that MICA*008 can be transferred by vesicles to NK cells causing fratricide. Focusing on MM as a clinically and biologically relevant model of tumour-NK cell interactions, we found enrichment of EVs expressing MICA in the bone marrow of a cohort of patients. All together our results suggest that the accumulation of NKG2D ligands associated to vesicles in the tumour microenvironment could favour the suppression of NK cell activity either by NKG2D down-modulation or by fratricide of NK cell dressed with EV-derived NKG2D ligands.
Asunto(s)
Vesículas Extracelulares/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Vigilancia Inmunológica , Células Asesinas Naturales/inmunología , Mieloma Múltiple/inmunología , Anciano , Anciano de 80 o más Años , Médula Ósea/inmunología , Muerte Celular/inmunología , Línea Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Inmunomodulación , Interferón gamma/metabolismo , Ligandos , Masculino , Persona de Mediana Edad , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Escape del TumorRESUMEN
α-hemolysin (HlyA) of E. coli binds irreversibly to human erythrocytes and induces cell swelling, ultimately leading to hemolysis. We characterized the mechanism involved in water transport induced by HlyA and analyzed how swelling and hemolysis might be coupled. Osmotic water permeability (Pf) was assessed by stopped-flow light scattering. Preincubation with HlyA strongly reduced Pf in control- and aquaporin 1-null red blood cells, although the relative Pf decrease was similar in both cell types. The dynamics of cell volume and hemolysis on RBCs was assessed by electrical impedance, light dispersion and hemoglobin release. Results show that HlyA induced erythrocyte swelling, which is enhanced by purinergic signaling, and is coupled to osmotic hemolysis. We propose a mathematical model of HlyA activity where the kinetics of cell volume and hemolysis in human erythrocytes depend on the flux of osmolytes across the membrane, and on the maximum volume that these cells can tolerate. Our results provide new insights for understanding signaling and cytotoxicity mediated by HlyA in erythrocytes.
Asunto(s)
Tamaño de la Célula , Eritrocitos/citología , Eritrocitos/fisiología , Proteínas de Escherichia coli/farmacología , Proteínas Hemolisinas/farmacología , Modelos Biológicos , Adenosina Trifosfato/metabolismo , Biomarcadores , Muerte Celular/efectos de los fármacos , Muerte Celular/inmunología , Relación Dosis-Respuesta a Droga , Proteínas de Escherichia coli/inmunología , Proteínas Hemolisinas/inmunología , Hemólisis , Interacciones Huésped-Patógeno , Humanos , Cinética , PermeabilidadRESUMEN
In humans, over-activation of innate immunity in response to viral or bacterial infections often causes severe illness and death. Furthermore, similar mechanisms related to innate immunity can cause pathogenesis and death in sepsis, massive trauma (including surgery and burns), ischemia/reperfusion, some toxic lesions, and viral infections including COVID-19. Based on the reviewed observations, we suggest that such severe outcomes may be manifestations of a controlled suicidal strategy protecting the entire population from the spread of pathogens and from dangerous pathologies rather than an aberrant hyperstimulation of defense responses. We argue that innate immunity may be involved in the implementation of an altruistic programmed death of an organism aimed at increasing the well-being of the whole community. We discuss possible ways to suppress this atavistic program by interfering with innate immunity and suggest that combating this program should be a major goal of future medicine.
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Altruismo , Apoptosis/inmunología , Inmunidad Innata/inmunología , Animales , COVID-19/inmunología , Muerte Celular/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Humanos , Inflamasomas/inmunología , Inflamación/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Transducción de Señal/inmunologíaRESUMEN
Mammals have evolved sophisticated host cell death signaling pathways as an important immune mechanism to recognize and eliminate cell intruders before they establish their replicative niche. However, intracellular bacterial pathogens that have co-evolved with their host have developed a multitude of tactics to counteract this defense strategy to facilitate their survival and replication. This requires manipulation of pro-death and pro-survival host signaling pathways during infection. Obligate intracellular bacterial pathogens are organisms that absolutely require an eukaryotic host to survive and replicate, and therefore they have developed virulence factors to prevent diverse forms of host cell death and conserve their replicative niche. This review encapsulates our current understanding of these host-pathogen interactions by exploring the most relevant findings of Anaplasma spp., Chlamydia spp., Rickettsia spp. and Coxiella burnetii modulating host cell death pathways. A detailed comprehension of the molecular mechanisms through which these obligate intracellular pathogens manipulate regulated host cell death will not only increase the current understanding of these difficult-to-study pathogens but also provide insights into new tools to study regulated cell death and the development of new therapeutic approaches to control infection.
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Fenómenos Fisiológicos Bacterianos , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno , Animales , Biomarcadores , Muerte Celular/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Espacio Intracelular/inmunología , Espacio Intracelular/metabolismo , Espacio Intracelular/microbiología , Lisosomas/inmunología , Lisosomas/metabolismo , Lisosomas/microbiología , Viabilidad Microbiana/inmunología , Estrés Oxidativo , Fagocitosis , Especificidad de la Especie , Factores de VirulenciaRESUMEN
Cell death is an essential immunological apparatus of host defense, but dysregulation of mutually inclusive cell deaths poses severe threats during microbial and parasitic infections leading to deleterious consequences in the pathological progression of infectious diseases. Nucleotide-binding oligomerization domain (NOD)-Leucine-rich repeats (LRR)-containing receptors (NLRs), also called nucleotide-binding oligomerization (NOD)-like receptors (NLRs), are major cytosolic pattern recognition receptors (PRRs), their involvement in the orchestration of innate immunity and host defense against bacteria, viruses, fungi and parasites, often results in the cleavage of gasdermin and the release of IL-1ß and IL-18, should be tightly regulated. NLRs are functionally diverse and tissue-specific PRRs expressed by both immune and non-immune cells. Beyond the inflammasome activation, NLRs are also involved in NF-κB and MAPK activation signaling, the regulation of type I IFN (IFN-I) production and the inflammatory cell death during microbial infections. Recent advancements of NLRs biology revealed its possible interplay with pyroptotic cell death and inflammatory mediators, such as caspase 1, caspase 11, IFN-I and GSDMD. This review provides the most updated information that caspase 8 skews the NLRP3 inflammasome activation in PANoptosis during pathogen infection. We also update multidimensional roles of NLRP12 in regulating innate immunity in a content-dependent manner: novel interference of NLRP12 on TLRs and NOD derived-signaling cascade, and the recently unveiled regulatory property of NLRP12 in production of type I IFN. Future prospects of exploring NLRs in controlling cell death during parasitic and microbial infection were highlighted.
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Infecciones/inmunología , Proteínas NLR/fisiología , Enfermedades Parasitarias/inmunología , Animales , Muerte Celular/inmunología , Interacciones Microbiota-Huesped , Interacciones Huésped-Parásitos , Humanos , Mediadores de Inflamación/metabolismo , Proteínas NLR/genética , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal , Virus/inmunologíaRESUMEN
Leptin, a hormone that is predominantly produced by adipose tissue, is closely associated with various liver diseases. However, there is a lack of understanding as to whether leptin directly induces cytotoxic effects in hepatocytes as well as the mechanisms that are involved. Inflammasomes, which are critical components in the innate immune system, have been recently shown to modulate cell death. In this study, we examined the effect of leptin on the viability of rat hepatocytes and the underlying mechanisms, with a particular focus on the role of inflammasomes activation. Leptin treatment induced cytotoxicity in rat hepatocytes, as determined by decreased cell viability, increased caspase-3 activity, and the enhanced release of lactate dehydrogenase. NLRP3 inflammasomes were activated by leptin both in vitro and in vivo, as determined by the maturation of interleukin-1ß and caspase-1, and the increased expression of inflammasome components, including NLRP3 and ASC. Mechanistically, leptin-induced inflammasome activation is mediated via the axis of ROS production, ER stress, and autophagy. Notably, the inhibition of inflammasomes by treatment with the NLRP3 inhibitor or the IL-1 receptor antagonist protected the hepatocytes from leptin-induced cell death. Together, these results indicate that leptin exerts cytotoxic effects in hepatocytes, at least in part, via the activation of NLRP3 inflammasomes.
Asunto(s)
Autofagia/genética , Inflamasomas/genética , Leptina/genética , Hepatopatías/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Tejido Adiposo/inmunología , Animales , Caspasa 3/genética , Muerte Celular/genética , Muerte Celular/inmunología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/genética , Hepatocitos/inmunología , Hepatocitos/patología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inflamasomas/inmunología , Interleucina-1beta/genética , Hepatopatías/inmunología , Hepatopatías/patología , Piroptosis/genética , Ratas , Receptores de Interleucina-1/genética , Transducción de Señal/genéticaRESUMEN
Necroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL). However, neither the exact protein composition, nor the impact, of necroptotic EVs have been delineated. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated and analyzed by mass spectrometry-based proteomics. A total of 3337 proteins were identified, sharing a high degree of similarity with exosome proteome databases, and clearly distinguishing necroptotic and control EVs. A total of 352 proteins were significantly upregulated in the necroptotic EVs. Among these were MLKL and caspase-8, as validated by immunoblot. Components of the ESCRTIII machinery and inflammatory signaling were also upregulated in the necroptotic EVs, as well as currently unreported components of vesicle formation and transport, and necroptotic signaling pathways. Moreover, we found that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we uncovered that necroptotic EVs contain tumor neoantigens, and are enriched with components of antigen processing and presentation. In summary, our study reveals a new layer of regulation during the early stage of necroptosis, mediated by the secretion of specific EVs that influences the microenvironment and may instigate innate and adaptive immune responses. This study sheds light on new potential players in necroptotic signaling and its related EVs, and uncovers the functional tasks accomplished by the cargo of these necroptotic EVs.