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JCI Insight Dec 2021Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and...
Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and depressive mice. Pyroptosis is a recently discovered form of programmed cell death depending on Caspase-gasdermin D (Casp-GSDMD), which is involved in multiple neuropsychiatric diseases. However, the involvement of pyroptosis in the onset of MDD and glial pathological injury remains obscure. Here, we observed that depressive mice showed astrocytic pyroptosis, which was responsible for astrocyte loss, and selective serotonin reuptake inhibitor (SSRI) treatment could attenuate the pyroptosis induced by the chronic mild stress (CMS) model. Genetic KO of GSDMD, Casp-1, and astrocytic NOD-like receptor protein 3 (NLRP3) inflammasome in mice alleviated depression-like behaviors and inhibited the pyroptosis-associated protein expression. In contrast, overexpression of astrocytic GSDMD-N-terminal domain (GSDMD-N) in the hippocampus could abolish the improvement of behavioral alterations in GSDMD-deficient mice. This work illustrates that targeting the NLRP3/Casp-1/GSDMD-mediated pyroptosis may provide potential therapeutic benefits to stress-related astrocyte loss in the pathogenesis of depression.
Topics: Animals; Astrocytes; Caspase 1; Depression; Disease Models, Animal; Humans; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 34877938
DOI: 10.1172/jci.insight.146852 -
Frontiers in Immunology 2022The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional... (Review)
Review
The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional consequences of several key cell death pathways. Currently, the most intensively investigated programmed cell death (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, which has been discovered to play crucial roles in modulating the immunosuppressive tumor microenvironment (TME) and determining clinical outcomes of the cancer therapeutic approaches. PCD can play dual roles, either pro-tumor or anti-tumor, partly depending on the intracellular contents released during the process. PCD also regulates the enrichment of effector or regulatory immune cells, thus participating in fine-tuning the anti-tumor immunity in the TME. In this review, we focused primarily on apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, discussed the released molecular messengers participating in regulating their intricate crosstalk with the immune response in the TME, and explored the immunological consequence of PCD and its implications in future cancer therapy developments.
Topics: Apoptosis; Ferroptosis; Humans; Necroptosis; Neoplasms; Pyroptosis; Tumor Microenvironment
PubMed: 35432318
DOI: 10.3389/fimmu.2022.847345 -
Frontiers in Cellular and Infection... 2020Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for... (Review)
Review
Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death-pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.
Topics: Apoptosis; Humans; Necroptosis; Phylogeny; Pyroptosis
PubMed: 32582562
DOI: 10.3389/fcimb.2020.00238 -
Theranostics 2021In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is... (Review)
Review
In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.
Topics: Animals; Apoptosis; Autophagy; Ferroptosis; Humans; Immunotherapy; Inflammasomes; Inflammation; Necroptosis; Neoplasms; Pyroptosis; Tumor Microenvironment
PubMed: 34522213
DOI: 10.7150/thno.62521 -
Immunity Feb 2023The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations...
The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations exacerbate inflammation has not been explored. Here, using antibiotic treatment and fecal microbial transfers, we showed that sepsis susceptibility is driven by pregnancy-induced changes to gut microbiome in mice and humans. Integrative multiomics and genetically engineered bacteria revealed that reduced Parabacteroides merdae (P. merdae) abundance during pregnancy led to decreased formononetin (FMN) and increased macrophage death. Mechanistically, FMN inhibited macrophage pyroptosis by suppressing nuclear accumulation of hnRNPUL2 and subsequent binding to the Nlrp3 promoter. Treatment with FMN or deletion of murine hnRNPUL2 protected against septic inflammation. Intestinal abundances of P. merdae and FMN inversely correlated with the progression of septic patients. Our data reveal a microbe-immune axis that is disrupted in pregnant septic hosts, highlighting the potential of the FMN-hnRNPUL2-NLRP3 axis in providing promising therapeutic strategies for sepsis.
Topics: Pregnancy; Female; Humans; Animals; Mice; Gastrointestinal Microbiome; Pyroptosis; NLR Family, Pyrin Domain-Containing 3 Protein; Macrophages; Sepsis; Inflammation
PubMed: 36792573
DOI: 10.1016/j.immuni.2023.01.015 -
Frontiers in Immunology 2023PANoptosis, a new research hotspot at the moment, is a cell death pattern in which pyroptosis, apoptosis, and necroptosis all occur in the same cell population. In... (Review)
Review
PANoptosis, a new research hotspot at the moment, is a cell death pattern in which pyroptosis, apoptosis, and necroptosis all occur in the same cell population. In essence, PANoptosis is a highly coordinated and dynamically balanced programmed inflammatory cell death pathway that combines the main features of pyroptosis, apoptosis, and necroptosis. Many variables, such as infection, injury, or self-defect, may be involved in the occurrence of PANoptosis, with the assembly and activation of the PANoptosome being the most critical. PANoptosis has been linked to the development of multiple systemic diseases in the human body, including infectious diseases, cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, it is necessary to clarify the process of occurrence, the regulatory mechanism of PANoptosis, and its relation to diseases. In this paper, we summarized the differences and relations between PANoptosis and the three types of programmed cell death, and emphatically expounded molecular mechanism and regulatory patterns of PANoptosis, with the expectation of facilitating the application of PANoptosis regulation in disease treatment.
Topics: Humans; Apoptosis; Pyroptosis; Cell Death; Necroptosis; Neurodegenerative Diseases
PubMed: 36845112
DOI: 10.3389/fimmu.2023.1120034 -
Trends in Cancer May 2023Induction of cell death is inexorably linked with cancer therapy, but this can also initiate wound-healing processes that have been linked to cancer progression and... (Review)
Review
Induction of cell death is inexorably linked with cancer therapy, but this can also initiate wound-healing processes that have been linked to cancer progression and therapeutic resistance. Here we describe the contribution of apoptosis and the lytic cell death pathways in the response to therapy (including chemotherapy and immunotherapy). We also discuss how necroptosis, pyroptosis, and ferroptosis function to promote tumor immunogenicity, along with emerging findings that these same forms of death can paradoxically contribute to immune suppression and tumor progression. Understanding the duality of cell death in cancer may allow for the development of therapeutics that shift the balance towards regression.
Topics: Humans; Cell Death; Apoptosis; Pyroptosis; Neoplasms; Immunity
PubMed: 36841748
DOI: 10.1016/j.trecan.2023.02.001 -
Pharmacology & Therapeutics Apr 2022Programmed cell death (PCD) is an essential part of organismal development and plays fundamental roles in host defense against pathogens and the maintenance of... (Review)
Review
Programmed cell death (PCD) is an essential part of organismal development and plays fundamental roles in host defense against pathogens and the maintenance of homeostasis. However, excess activation of PCD pathways has proven to be detrimental and can drive disease. Additionally, resistance to PCD can also contribute to disease development. Modulation of PCD, therefore, has great therapeutic potential in a wide range of diseases, including infectious, neurodegenerative, autoinflammatory, and metabolic diseases and cancer. Nevertheless, manipulation of cell death and inflammation for therapeutic intervention is a delicate process, highly specific to the context of the disease of interest, making the selection of the appropriate target molecule crucially important. Several PCD pathways are associated with innate immunity, including pyroptosis, apoptosis, necroptosis, and PANoptosis, which is defined as an inflammatory PCD pathway with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. All of these PCD pathways are regulated by upstream sensors and signaling cascades that assemble multimeric complexes to serve as activation platforms for downstream molecules; these sensors and signaling molecules provide attractive target points for therapeutic intervention. Here, we discuss the molecular mechanisms of innate immune-mediated cell death in health and disease, with a particular focus on the molecules putatively involved in the formation of the PANoptosome and the induction of inflammatory cell death. Further, we discuss the implications and feasibility of targeting these molecules to improve disease outcomes, as well as current clinical approaches.
Topics: Apoptosis; Cell Death; Humans; Immunity, Innate; Necroptosis; Pyroptosis
PubMed: 34619283
DOI: 10.1016/j.pharmthera.2021.108010 -
Current Opinion in Microbiology Feb 2021The immune system has evolved multiple mechanisms to restrict microbial infections and regulate inflammatory responses. Without appropriate regulation, infection-induced... (Review)
Review
The immune system has evolved multiple mechanisms to restrict microbial infections and regulate inflammatory responses. Without appropriate regulation, infection-induced inflammatory pathology can be deadly. The innate immune system recognizes the microbial molecules conserved in many pathogens and engages a rapid response by producing inflammatory mediators and activating programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis. Activation of pattern recognition receptors, in combination with inflammatory cytokine-induced signaling through death domain-containing receptors, initiates a highly interconnected cell death process called PANoptosis (pyroptosis, apoptosis, necroptosis). Broadly speaking, PANoptosis is critical for restricting a wide range of pathogens (including bacteria, viruses, fungi, and parasites), which we describe in this review. We propose that re-examining the role of cell death and inflammatory cytokines through the lens of PANoptosis will advance our understanding of host-pathogen evolution and may reveal new treatment strategies for controlling a wide range of infectious diseases.
Topics: Apoptosis; Bacterial Physiological Phenomena; Biological Evolution; Cell Death; Fungi; Host-Pathogen Interactions; Infections; Necroptosis; Pyroptosis; Virus Physiological Phenomena
PubMed: 32829024
DOI: 10.1016/j.mib.2020.07.012 -
Experimental & Molecular Medicine Aug 2023Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically,... (Review)
Review
Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.
Topics: Apoptosis; Mitochondria; Cell Death; Pyroptosis
PubMed: 37612409
DOI: 10.1038/s12276-023-01046-5