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Frontiers in Immunology 2021COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular... (Review)
Review
COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.
Topics: Adenosine; Alarmins; Animals; COVID-19; Humans; Inflammation; Inflammation Mediators; Multiple Organ Failure; Patient Acuity; Signal Transduction; Toll-Like Receptors
PubMed: 34456928
DOI: 10.3389/fimmu.2021.720192 -
Journal of Innate Immunity 2023The innate immune system, as the host's first line of defense against intruders, plays a critical role in recognizing, identifying, and reacting to a wide range of... (Review)
Review
The innate immune system, as the host's first line of defense against intruders, plays a critical role in recognizing, identifying, and reacting to a wide range of microbial intruders. There is increasing evidence that mitochondrial stress is a major initiator of innate immune responses. When mitochondria's integrity is disrupted or dysfunction occurs, the mitochondria's contents are released into the cytosol. These contents, like reactive oxygen species, mitochondrial DNA, and double-stranded RNA, among others, act as damage-related molecular patterns (DAMPs) that can bind to multiple innate immune sensors, particularly pattern recognition receptors, thereby leading to inflammation. To avoid the production of DAMPs, in addition to safeguarding organelles integrity and functionality, mitochondria may activate mitophagy or apoptosis. Moreover, mitochondrial components and specific metabolic regulations modify properties of innate immune cells. These include macrophages, dendritic cells, innate lymphoid cells, and so on, in steady state or in stimulation that are involved in processes ranging from the tricarboxylic acid cycle to oxidative phosphorylation and fatty acid metabolism. Here we provide a brief summary of mitochondrial DAMPs' initiated and potentiated inflammatory response in the innate immune system. We also provide insights into how the state of activation, differentiation, and functional polarization of innate immune cells can be influenced by alteration to the metabolic pathways in mitochondria.
Topics: Humans; Immunity, Innate; Lymphocytes; Mitochondria; Inflammation; DNA, Mitochondrial; Alarmins
PubMed: 37666239
DOI: 10.1159/000533602 -
Frontiers in Immunology 2023HMGB1 that belongs to the High Mobility Group-box superfamily, is a nonhistone chromatin associated transcription factor. It is present in the nucleus of eukaryotes and... (Review)
Review
HMGB1 that belongs to the High Mobility Group-box superfamily, is a nonhistone chromatin associated transcription factor. It is present in the nucleus of eukaryotes and can be actively secreted or passively released by kinds of cells. HMGB1 is important for maintaining DNA structure by binding to DNA and histones, protecting it from damage. It also regulates the interaction between histones and DNA, affecting chromatin packaging, and can influence gene expression by promoting nucleosome sliding. And as a DAMP, HMGB1 binding to RAGE and TLRs activates NF-κB, which triggers the expression of downstream genes like IL-18, IL-1β, and TNF-α. HMGB1 is known to be involved in numerous physiological and pathological processes. Recent studies have demonstrated the significance of HMGB1 as DAMPs in the female reproductive system. These findings have shed light on the potential role of HMGB1 in the pathogenesis of diseases in female reproductive system and the possibilities of HMGB1-targeted therapies for treating them. Such therapies can help reduce inflammation and metabolic dysfunction and alleviate the symptoms of reproductive system diseases. Overall, the identification of HMGB1 as a key player in disease of the female reproductive system represents a significant breakthrough in our understanding of these conditions and presents exciting opportunities for the development of novel therapies.
Topics: Female; Humans; Alarmins; Chromatin; Genitalia, Female; Histones; HMGB1 Protein; Tumor Necrosis Factor-alpha
PubMed: 37691930
DOI: 10.3389/fimmu.2023.1238785 -
Oncoimmunology Dec 2020Ferroptosis is an iron-dependent form of non-apoptotic cell death that has recently been attributed with antitumor immune effects. Thus, early ferroptotic cells...
Ferroptosis is an iron-dependent form of non-apoptotic cell death that has recently been attributed with antitumor immune effects. Thus, early ferroptotic cells underwent immunogenic cell death that was accompanied by the emission of damage-associated molecular patterns (DAMPs) and triggered dendritic cell maturation in vitro. Furthermore, ferroptotic cells were able to vaccinate against a rechallenge with fibrosarcoma in preclinical models.
Topics: Alarmins; Ferroptosis; Fibrosarcoma; Humans; Immunogenic Cell Death; Iron
PubMed: 33457081
DOI: 10.1080/2162402X.2020.1862949 -
Plant Physiology Apr 2020Plants use specific receptor proteins on the cell surface to detect hostderived danger signals released in response to attacks by pathogens or herbivores and activate... (Review)
Review
Plants use specific receptor proteins on the cell surface to detect hostderived danger signals released in response to attacks by pathogens or herbivores and activate immune responses against them
Topics: Adenosine Triphosphate; Alarmins; Models, Biological; Plants; Receptors, Cell Surface
PubMed: 31907298
DOI: 10.1104/pp.19.01242 -
American Journal of Transplantation :... Feb 2017Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical... (Review)
Review
Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients.
Topics: Alarmins; Animals; Graft vs Host Disease; Humans; Receptors, Immunologic; Transplantation, Homologous
PubMed: 27232285
DOI: 10.1111/ajt.13887 -
Clinical and Translational Medicine Apr 2023Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the...
BACKGROUND
Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS.
METHODS
Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS.
RESULTS
We provide evidence that loss of Ca signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca homeostasis that inhibited alarmin release thereby reverting the pSS phenotype.
CONCLUSIONS
These results indicate that loss of Ca signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.
Topics: Humans; Animals; Mice; Sjogren's Syndrome; Alarmins; Salivary Glands; Saliva; Phenotype
PubMed: 37006181
DOI: 10.1002/ctm2.1228 -
International Journal of Molecular... Feb 2022Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells.... (Review)
Review
Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.
Topics: Alarmins; Diabetic Retinopathy; Humans; Inflammation; Receptor for Advanced Glycation End Products; Toll-Like Receptors
PubMed: 35269741
DOI: 10.3390/ijms23052591 -
Translational Research : the Journal of... Jul 2022Systemic lupus erythematosus (SLE) is a chronic and often progressive autoimmune disorder marked clinically by a variable constellation of symptoms including fatigue,... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic and often progressive autoimmune disorder marked clinically by a variable constellation of symptoms including fatigue, rash, joint pains, and kidney damage. The lungs, heart, gastrointestinal system, and brain can also be impacted, and individuals with lupus are at higher risk for atherosclerosis, thrombosis, thyroid disease, and other disorders associated with chronic inflammation . Autoimmune diseases are marked by erroneous immune responses in which the target of the immune response is a "self"-antigen, or autoantigen, driven by the development of antigen-specific B or T cells that have overcome the normal systems of self-tolerance built into the development of B and T cells. SLE is specifically characterized by the production of autoantibodies against nucleic acids and their binding proteins, including anti-double stranded DNA, anti-Smith (an RNA binding protein), and many others . These antibodies bind their nuclear-derived antigens to form immune complexes that cause injury and scarring through direct deposition in tissues and activation of innate immune cells . In over 50% of SLE patients, immune complex aggregation in the kidneys drives intrarenal inflammation and injury and leads to lupus nephritis, a progressive destruction of the glomeruli that is one of the most common causes of lupus-related death . To counter this pathology increasing attention has turned to developing approaches to reduce the development and continued generation of such autoantibodies. In particular, the molecular and cellular events that lead to long term, continuous activation of such autoimmune responses have become the focus of new therapeutic strategies to limit renal and other pathologies in lupus patients. The focus of this review is to consider how the innate immune system is involved in the development and progression of lupus nephritis and how a novel approach to inhibit innate immune activation by neutralizing the activators of this response, called Damage Associated Molecular Patterns, may represent a promising approach to treat this and other autoimmune disorders.
Topics: Alarmins; Autoantibodies; Humans; Inflammation; Lupus Erythematosus, Systemic; Lupus Nephritis; Nucleic Acids
PubMed: 35245691
DOI: 10.1016/j.trsl.2022.02.007 -
Cells Oct 2020Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known... (Review)
Review
Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group box protein 1, S100 proteins, heat shock proteins, nucleic acids, histones, nucleosomes, and monosodium urate microcrystals are thought to be alarmins. They are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors. Being principal sterile inflammation triggering agents, alarmins are considered biomarkers and therapeutic targets. They are recognized by host cells and prime the innate immune system toward cell death and distress. In stroke, alarmins act as mediators initiating the inflammatory response after the release from the cellular components of the infarct core and penumbra. Increased c-Jun N-terminal kinase (JNK) phosphorylation may be involved in the mechanism of stress-induced release of alarmins. Putative crosstalk between the alarmin-associated pathways and JNK signaling seems to be inherently interwoven. This review outlines the role of alarmins/JNK-signaling in cerebral neurovascular inflammation and summarizes the complex response of cells to alarmins. Emerging anti-JNK and anti-alarmin drug treatment strategies are discussed.
Topics: Alarmins; Animals; Anti-Inflammatory Agents; Biomarkers; Disease Susceptibility; Humans; JNK Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Neurodegenerative Diseases; Neurogenic Inflammation; Signal Transduction
PubMed: 33114371
DOI: 10.3390/cells9112350