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Nature Reviews. Immunology Mar 2023Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the... (Review)
Review
Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.
Topics: Humans; Mitochondria; Inflammation; Alarmins; Neoplasms
PubMed: 35879417
DOI: 10.1038/s41577-022-00760-x -
Experimental & Molecular Medicine Feb 2022High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA... (Review)
Review
High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA chaperone that maintains the structure and function of chromosomes. In the cytoplasm, HMGB1 can promote autophagy by binding to BECN1 protein. After its active secretion or passive release, extracellular HMGB1 usually acts as a damage-associated molecular pattern (DAMP) molecule, regulating inflammation and immune responses through different receptors or direct uptake. The secretion and release of HMGB1 is fine-tuned by a variety of factors, including its posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, and methylation) and the molecular machinery of cell death (e.g., apoptosis, pyroptosis, necroptosis, alkaliptosis, and ferroptosis). In this minireview, we introduce the basic structure and function of HMGB1 and focus on the regulatory mechanism of HMGB1 secretion and release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases and tissue damage.
Topics: Alarmins; Apoptosis; Autophagy; Cell Death; HMGB1 Protein
PubMed: 35217834
DOI: 10.1038/s12276-022-00736-w -
Apoptosis : An International Journal on... Apr 2021Damage-associated molecular patterns (DAMPs) are endogenous molecules which foment inflammation and are associated with disorders in sepsis and cancer. Thus,... (Review)
Review
Damage-associated molecular patterns (DAMPs) are endogenous molecules which foment inflammation and are associated with disorders in sepsis and cancer. Thus, therapeutically targeting DAMPs has potential to provide novel and effective treatments. When establishing anti-DAMP strategies, it is important not only to focus on the DAMPs as inflammatory mediators but also to take into account the underlying mechanisms of their release from cells and tissues. DAMPs can be released passively by membrane rupture due to necrosis/necroptosis, although the mechanisms of release appear to differ between the DAMPs. Other types of cell death, such as apoptosis, pyroptosis, ferroptosis and NETosis, can also contribute to DAMP release. In addition, some DAMPs can be exported actively from live cells by exocytosis of secretory lysosomes or exosomes, ectosomes, and activation of cell membrane channel pores. Here we review the shared and DAMP-specific mechanisms reported in the literature for high mobility group box 1, ATP, extracellular cold-inducible RNA-binding protein, histones, heat shock proteins, extracellular RNAs and cell-free DNA.
Topics: Alarmins; Animals; Apoptosis; Cell Death; Circulating MicroRNA; Exocytosis; Exosomes; HMGB1 Protein; Heat-Shock Proteins; Histones; Humans; Inflammation; Necrosis; Sepsis
PubMed: 33713214
DOI: 10.1007/s10495-021-01663-3 -
Molecular Oncology Dec 2020Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic... (Review)
Review
Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. Remarkably, subcutaneous injection of dying tumor cells undergoing ICD has been shown to provoke anticancer vaccine effects in vivo. DAMPs include the cell surface exposure of calreticulin (CRT) and heat-shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), type I IFNs and members of the IL-1 cytokine family. In this review, we discuss the cell death modalities connected to ICD, the DAMPs exposed during ICD, and the mechanism by which they activate the immune system. Finally, we discuss the therapeutic potential and challenges of harnessing ICD in cancer immunotherapy.
Topics: Alarmins; Animals; Endoplasmic Reticulum Stress; Humans; Immunity; Immunogenic Cell Death; Neoplasms; T-Lymphocytes
PubMed: 33179413
DOI: 10.1002/1878-0261.12851 -
Translational Research : the Journal of... Dec 2018Mitochondria are functionally versatile organelles. In addition to their conventional role of meeting the cell's energy requirements, mitochondria also actively regulate... (Review)
Review
Mitochondria are functionally versatile organelles. In addition to their conventional role of meeting the cell's energy requirements, mitochondria also actively regulate innate immune responses against infectious and sterile insults. Components of mitochondria, when released or exposed in response to dysfunction or damage, can be directly recognized by receptors of the innate immune system and trigger an immune response. In addition, despite initiation that may be independent from mitochondria, numerous innate immune responses are still subject to mitochondrial regulation as discrete steps of their signaling cascades occur on mitochondria or require mitochondrial components. Finally, mitochondrial metabolites and the metabolic state of the mitochondria within an innate immune cell modulate the precise immune response and shape the direction and character of that cell's response to stimuli. Together, these pathways result in a nuanced and very specific regulation of innate immune responses by mitochondria.
Topics: Alarmins; Animals; DNA, Mitochondrial; Humans; Immunity, Innate; Mitochondria; Models, Biological; Signal Transduction
PubMed: 30165038
DOI: 10.1016/j.trsl.2018.07.014 -
Current Biology : CB Nov 2020Iron is an essential micronutrient for microorganisms, plants, animals, and humans. However, iron overload can damage the organism through a variety of mechanisms,...
Iron is an essential micronutrient for microorganisms, plants, animals, and humans. However, iron overload can damage the organism through a variety of mechanisms, including the induction of cell death. Ferroptosis is defined as an iron-dependent form of regulated cell death caused by unrestricted lipid peroxidation and subsequent membrane damage. Ferroptosis can be triggered through either the extrinsic or the intrinsic pathway. The extrinsic pathway is initiated through the regulation of transporters (e.g., inhibition of the amino acid antiporter system xc or activation of the iron transporters transferrin and lactotransferrin), whereas the intrinsic pathway is mainly induced by blocking the expression or activity of intracellular antioxidant enzymes, such as glutathione peroxidase 4 (GPX4). In addition to small-molecule compounds and drugs, certain stresses (e.g., high temperature, low temperature, hypoxia, and radiation) induce ferroptotic cell death. The abnormal regulation of this process, which is connected to protein degradation pathways, such as autophagy and the ubiquitin-proteasome system, is associated with various pathological conditions, including acute tissue damage, infection, cancer, and neurodegeneration. Here, we discuss the core process and regulation of ferroptosis in mammalian cells, as well as its therapeutic implications in disease.
Topics: Alarmins; Animals; Autophagy; Fatty Acids; Ferroptosis; Glutathione; Humans; Iron; Lipid Peroxidation; Neoplasms; Neurodegenerative Diseases; Nitric Oxide; Phospholipid Hydroperoxide Glutathione Peroxidase; Proteasome Endopeptidase Complex; Proteolysis; Reactive Oxygen Species; Stress, Physiological; Ubiquitination
PubMed: 33142092
DOI: 10.1016/j.cub.2020.09.068 -
Frontiers in Immunology 2019Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the... (Review)
Review
Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.
Topics: Adenosine Triphosphate; Alarmins; Animals; Disease Susceptibility; Extracellular Traps; HMGB1 Protein; Histones; Humans; Neutrophils; Protein Binding; Sepsis; Signal Transduction
PubMed: 31736963
DOI: 10.3389/fimmu.2019.02536 -
Frontiers in Immunology 2020The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and... (Review)
Review
The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and caspase-1. This complex is crucial to the host's defense against microbes as it promotes IL-1β and IL-18 secretion and induces pyroptosis. NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dependent antiviral immune responses and facilitates viral eradication. Meanwhile, several viruses have evolved elaborate strategies to evade the immune system by targeting the NLRP3 inflammasome. In this review, we will focus on the crosstalk between the NLRP3 inflammasome and viruses, provide an overview of viral infection-induced NLRP3 inflammasome activation, and the immune escape strategies of viruses through their modulation of the NLRP3 inflammasome activity.
Topics: Alarmins; Animals; Humans; Immune Evasion; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pathogen-Associated Molecular Pattern Molecules; Signal Transduction; Virus Diseases; Viruses
PubMed: 32133002
DOI: 10.3389/fimmu.2020.00211 -
International Journal of Molecular... Oct 2019Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying... (Review)
Review
Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.
Topics: Adenosine; Alarmins; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis; Arthritis, Rheumatoid; Cytokines; Folic Acid; HMGB1 Protein; Humans; Immunity, Innate; Inflammation; Matrix Metalloproteinases; Methotrexate; NF-kappa B; Polyamines; Prostaglandins; Reactive Oxygen Species
PubMed: 31658782
DOI: 10.3390/ijms20205023 -
Frontiers in Immunology 2020High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and... (Review)
Review
High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damage-associated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.
Topics: Alarmins; Animals; Antigens, Neoplasm; HMGB1 Protein; Humans; Immunity, Innate; Inflammation; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Signal Transduction; Toll-Like Receptor 4
PubMed: 32265930
DOI: 10.3389/fimmu.2020.00484