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Clinical Therapeutics May 2016Alarmins are constitutively present endogenous molecules that essentially act as early warning signals for the immune system. We provide a brief overview of major... (Review)
Review
PURPOSE
Alarmins are constitutively present endogenous molecules that essentially act as early warning signals for the immune system. We provide a brief overview of major alarmins and highlight their roles in tumor immunity.
METHODS
We searched PubMed up to January 10, 2016, using alarmins and/or damage-associated molecular patterns (DAMPs), as key words. We selected and reviewed articles that focused on the discovery and functions of alarmin and their roles in tumor immunity.
FINDINGS
Alarmins are essentially endogenous immunostimulatory DAMP molecules that are exposed in response to danger (eg, infection or tissue injury) as a result of degranulation, cell death, or induction. They are sensed by chemotactic receptors and pattern recognition receptors to induce immune responses by promoting the recruitment and activation of leukocytes, particularly antigen-presenting cells.
IMPLICATIONS
Accumulating data suggest that certain alarmins, High-mobility group nucleosome-binding protein 1 (HMGN1) in particular, contribute to the generation of antitumor immunity. Some alarmins can also be used as cancer biomarkers. Therefore, alarmins can potentially be applied for our fight against cancers.
Topics: Alarmins; Animals; Biomedical Research; Humans; Mice; Neoplasms
PubMed: 27101817
DOI: 10.1016/j.clinthera.2016.03.021 -
Frontiers in Immunology 2023Most of the leading causes of death, such as cardiovascular diseases, cancer, dementia, neurodegenerative diseases, and many more, are associated with sterile... (Review)
Review
Most of the leading causes of death, such as cardiovascular diseases, cancer, dementia, neurodegenerative diseases, and many more, are associated with sterile inflammation, either as a cause or a consequence of these conditions. The ability to control the progression of inflammation toward tissue resolution before it becomes chronic holds significant clinical potential. During sterile inflammation, the initiation of inflammation occurs through damage-associated molecular patterns (DAMPs) in the absence of pathogen-associated molecules. Macrophages, which are primarily localized in the tissue, play a pivotal role in sensing DAMPs. Furthermore, macrophages can also detect and respond to resolution-associated molecular patterns (RAMPs) and specific pro-resolving mediators (SPMs) during sterile inflammation. Macrophages, being highly adaptable cells, are particularly influenced by changes in the microenvironment. In response to the tissue environment, monocytes, pro-inflammatory macrophages, and pro-resolution macrophages can modulate their differentiation state. Ultimately, DAMP and RAMP-primed macrophages, depending on the predominant subpopulation, regulate the balance between inflammatory and resolving processes. While sterile injury and pathogen-induced reactions may have distinct effects on macrophages, most studies have focused on macrophage responses induced by pathogens. In this review, which emphasizes available human data, we illustrate how macrophages sense these mediators by examining the expression of receptors for DAMPs, RAMPs, and SPMs. We also delve into the signaling pathways induced by DAMPs, RAMPs, and SPMs, which primarily contribute to the regulation of macrophage differentiation from a pro-inflammatory to a pro-resolution phenotype. Understanding the regulatory mechanisms behind the transition between macrophage subtypes can offer insights into manipulating the transition from inflammation to resolution in sterile inflammatory diseases.
Topics: Humans; Inflammation; Macrophages; Monocytes; Signal Transduction; Alarmins
PubMed: 37465676
DOI: 10.3389/fimmu.2023.1169560 -
Immunological Reviews Sep 2020Inflammasomes are macromolecular complexes formed in response to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) that... (Review)
Review
Inflammasomes are macromolecular complexes formed in response to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) that drive maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post-translational checkpoints. When these checkpoints are not properly imposed, undue inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL-1-targeted biologics, upstream targeting of inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating inflammasome activation in pathological conditions.
Topics: Alarmins; Humans; Inflammasomes; Interleukin-18; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 32770571
DOI: 10.1111/imr.12908 -
Frontiers in Immunology 2021Cancer immunotherapy has achieved great advancement in the past decades. Whereas, its response is largely limited in immunologically cold tumors, in an urgent need to be... (Review)
Review
Cancer immunotherapy has achieved great advancement in the past decades. Whereas, its response is largely limited in immunologically cold tumors, in an urgent need to be solve. In recent years, an increasing number of studies have shown that inducing immunogenic cell deaths (ICDs) is an attractive approach to activate antitumor immunity. Upon specific stress, cancer cells undergo ICDs and dying cancer cells release danger associated molecular patterns (DAMPs), produce neoantigens and trigger adaptive immunity. ICDs exert a cancer vaccine-like effect and Inducement of ICDs mimics process of cancer vaccination. In this review, we propose a concept of ICD-based cancer vaccines and summarize sources of ICD-based cancer vaccines and their challenges, which may broaden the understandings of ICD and cancer vaccines in cancer immunotherapy.
Topics: Alarmins; Animals; Cancer Vaccines; Humans; Immunogenic Cell Death; Neoplasms
PubMed: 34135914
DOI: 10.3389/fimmu.2021.697964 -
F1000Research 2018Schistosomiasis is a serious but neglected tropical infectious disease, afflicting more than 240 million people in 78 countries. Lack of an effective vaccine and... (Review)
Review
Schistosomiasis is a serious but neglected tropical infectious disease, afflicting more than 240 million people in 78 countries. Lack of an effective vaccine and obscuring disease mechanism could be the main hurdles to effectively control and eradicate this disease. A better understanding of the host-schistosome interaction is the key to clearing these hurdles. Recently, accumulating evidence shows that alarmin cytokines and microRNAs (miRNAs) are crucial regulators in the host-schistosome interaction. Alarmin cytokines are proven to be potent mechanisms driving type 2 immunity, which is the central disease mechanism of schistosomiasis. MiRNA deregulation is a hallmark of a variety of human diseases, including schistosomiasis. In this review, we summarize the research advances on the role of alarmin cytokines and miRNAs in the host-schistosome interaction.
Topics: Alarmins; Animals; Cytokines; Host-Pathogen Interactions; Humans; MicroRNAs; Schistosoma; Schistosomiasis
PubMed: 30345011
DOI: 10.12688/f1000research.15695.1 -
Frontiers in Immunology 2022HMGB1, a highly conserved non-histone nuclear protein, is widely expressed in mammalian cells. HMGB1 in the nucleus binds to the deoxyribonucleic acid (DNA) to regulate... (Review)
Review
HMGB1, a highly conserved non-histone nuclear protein, is widely expressed in mammalian cells. HMGB1 in the nucleus binds to the deoxyribonucleic acid (DNA) to regulate the structure of chromosomes and maintain the transcription, replication, DNA repair, and nucleosome assembly. HMGB1 is actively or passively released into the extracellular region during cells activation or necrosis. Extracellular HMGB1 as an alarmin can initiate immune response alone or combined with other substances such as nucleic acid to participate in multiple biological processes. It has been reported that HMGB1 is involved in various inflammatory responses and autoimmunity. This review article summarizes the physiological function of HMGB1, the post-translational modification of HMGB1, its interaction with different receptors, and its recent advances in rheumatic diseases and strategies for targeted therapy.
Topics: Alarmins; Animals; Cell Nucleus; HMGB1 Protein; Immunity; Mammals; Rheumatic Diseases
PubMed: 35250993
DOI: 10.3389/fimmu.2022.815257 -
Frontiers in Immunology 2023Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The... (Review)
Review
Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins.
Topics: Humans; Autoimmunity; Complement C1; HMGB1 Protein; Alarmins; Nucleosomes; Lupus Erythematosus, Systemic; Antibodies, Antinuclear; Autoantigens
PubMed: 37359557
DOI: 10.3389/fimmu.2023.1196544 -
Journal of Immunology Research 2020Pathogen-associated molecular patterns (PAMPs) are some nonspecific and highly conserved molecular structures of exogenous specific microbial pathogens, whose products... (Review)
Review
Pathogen-associated molecular patterns (PAMPs) are some nonspecific and highly conserved molecular structures of exogenous specific microbial pathogens, whose products can be recognized by pattern recognition receptor (PRR) on innate immune cells and induce an inflammatory response. Under physiological stress, activated or damaged cells might release some endogenous proteins that can also bind to PRR and cause a harmful aseptic inflammatory response. These endogenous proteins were named damage-associated molecular patterns (DAMPs) or alarmins. Indeed, alarmins can also play a beneficial role in the tissue repair in certain environments. Besides, some alarmin cytokines have been reported to have both nuclear and extracellular effects. This group of proteins includes high-mobility group box-1 protein (HMGB1), interleukin (IL)-33, IL-1, IL-1F7b, and IL-16. In this article, we review the involvement of nuclear alarmins such as HMGB1, IL-33, and IL-1 under physiological state or stress state and suggest a novel activity of these molecules as central initiators in the development of sterile inflammation.
Topics: Alarmins; Animals; Biomarkers; Cell Nucleus; Cytokines; Disease Susceptibility; HMGB1 Protein; Host-Pathogen Interactions; Humans; Inflammation; Inflammation Mediators
PubMed: 33344656
DOI: 10.1155/2020/7206451 -
Journal of Leukocyte Biology Jul 2019Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of... (Review)
Review
Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of intracellular CIRP (iCIRP) as a stress-response protein has been extensively studied. Recently, extracellular CIRP (eCIRP) was discovered to also have an important role, acting as a damage-associated molecular pattern, raising critical implications for the pathobiology of inflammatory diseases. During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-κB and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors. Studies with CIRP mice reveal protection against inflammation, implicating eCIRP to be a novel drug target. Anti-CIRP Ab or CIRP-derived small peptide may have effective therapeutic potentials in sepsis, acute lung injury, and organ ischemia/reperfusion injuries. The current review focuses on the pathobiology of eCIRP by emphasizing on signal transduction machineries, leading to discovering novel therapeutic interventions targeting eCIRP in various inflammatory diseases.
Topics: Alarmins; Animals; Endoplasmic Reticulum Stress; Humans; Inflammation; Inflammation Mediators; Neutrophils; RNA-Binding Proteins; Signal Transduction; Toll-Like Receptor 4
PubMed: 30645013
DOI: 10.1002/JLB.3MIR1118-443R -
Frontiers in Immunology 2022Skin acts as the primary interface between the body and the environment. The skin immune system is composed of a complex network of immune cells and factors that provide... (Review)
Review
Skin acts as the primary interface between the body and the environment. The skin immune system is composed of a complex network of immune cells and factors that provide the first line of defense against microbial pathogens and environmental insults. Alarmin cytokines mediate an intricate intercellular communication between keratinocytes and immune cells to regulate cutaneous immune responses. Proper functions of the type 2 alarmin cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, are paramount to the maintenance of skin homeostasis, and their dysregulation is commonly associated with allergic inflammation. In this review, we discuss recent findings on the complex regulatory network of type 2 alarmin cytokines that control skin immunity and highlight the mechanisms by which these cytokines regulate skin immune responses in host defense, chronic inflammation, and cancer.
Topics: Alarmins; Cytokines; Humans; Inflammation; Keratinocytes; Skin
PubMed: 35432341
DOI: 10.3389/fimmu.2022.876515