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Alarmin
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De Yang – One of the best experts on this subject based on the ideXlab platform.
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Alarmins and immunity
Immunological reviews, 2017Co-Authors: De Yang, Zhen Han, Joost J OppenheimAbstract:More than a decade has passed since the conceptualization of the “Alarmin” hypothesis. The Alarmin family has been expanding in terms of both number and the concept. It has recently become clear that Alarmins play important roles as initiators and participants in a diverse range of physiological and pathophysiological processes such as host defense, regulation of gene expression, cellular homeostasis, wound healing, inflammation, allergy, autoimmunity, and oncogenesis. Here, we provide a general view on the participation of Alarmins in the induction of innate and adaptive immune responses, as well as their contribution to tumor immuimmunity.
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Alarmins and Antitumor Immunity.
Clinical therapeutics, 2016Co-Authors: Yingjie Nie, De Yang, Joost J OppenheimAbstract:Abstract 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 immuimmunity. 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 immuimmunity. 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 protprotein 1 (HMGN1) in particular, contribute to the generation of antitumor immunity. Some Alarmins can also be used as cancer biombiomarkers. Therefore, Alarmins can potentially be applied for our fight against cancers.
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Harnessing the Alarmin HMGN1 for anticancer therapy.
Immunotherapy, 2015Co-Authors: De Yang, Michael Bustin, Joost J OppenheimAbstract:Incipient cancer cells formed as a result of mutations of oncogene(s), tumor suppressor gene(s) and/or DNA repair gene(s) develop into malignant tumors depending on three processes. They acquire a higher rate of mutation due to increased sensitivity to endogenous and exogenous mutagenic agents or due to a breakdown in one or several components of the DNA repair machinery [1]. They need to be induced to grow by hormones, cytokines and other mitogenic signals and achieve replicative immortality. Finally, the host’s immunosurveillance function fails because of immunoediting [2] and formation of an immunossupressive tumor microenvironment, resulting in preventing the immune control or rejection of the cancers [1,2]. Reagents that interfere with any of these processes have been identified as potential anticancer therapeutics [1]. We have shown the high mobility group nucleosome–binding protprotein 1 (HMGN1) to have a combination of activities that potentially counters the mutagenic and immunosuppressive properties of cancers. HMGN1 is a chromatin-binding nuclear protein and that can act as an extracellular Alarmin. In this respect, HMGN1 is similar to the well known Alarmin, HMGB1. Although HMGN1 and HMGB1 function both as chromatin binding protproteins and as Alarmins, they are otherwise completely distinct proteins, unrelated in amino acid sequence. Two biological activities of HMGN1 can potentially be harnessed as antitumor activities. First, inside the nucleus, HMGN1 acts as a chromatin modifier to regulate chromatin structure, gene expression and post-translational modification of core histones, all of which are factors that affect DNA repair and tumor progression [3]. Second, HMGN1 is released by nonleukocytes such as epithelial cells in response to injurious agents, changes in intracellular calcium and inflammatory stimulants. When released by the cells, extracellular HMGN1 function as a Th1-polarizing Alarmin that promotes the induction of innate and adaptive antitumor immune responses [4]. In the absence of nuclear HMGN1, cells become prone to mutagenic stimuli. Hmgn1 cells derived from HMGN1 knockout mice are hypersensitive to UV and ionizing irradiation, and show decreased capacity to repair DNA damage [5,6]. Consequently, Hmgn1 mice exhibit increased tumor formation in response to irradiation [7] or chemical carcinogens [8]. Even without treatment with exogenous DNA-damaging agents, Hmgn1 mice develop twice as many spontaneous tumors as their Hmgn1 littermates [7], supporting the notion that HMGN1 plays a role in DNA repair and the maintenance of genome stability. Given the requirement of multiple mutations in the course of cancer development [1,9], HMGN1 could potentially be used as a molecular target designed to counteract Harnessing the Alarmin HMGN1 for anticancer therapy
Joost J Oppenheim – One of the best experts on this subject based on the ideXlab platform.
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Alarmins and immunity
Immunological reviews, 2017Co-Authors: De Yang, Zhen Han, Joost J OppenheimAbstract:More than a decade has passed since the conceptualization of the “Alarmin” hypothesis. The Alarmin family has been expanding in terms of both number and the concept. It has recently become clear that Alarmins play important roles as initiators and participants in a diverse range of physiological and pathophysiological processes such as host defense, regulation of gene expression, cellular homeostasis, wound healing, inflammation, allergy, autoimmunity, and oncogenesis. Here, we provide a general view on the participation of Alarmins in the induction of innate and adaptive immune responses, as well as their contribution to tumor immunity.
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Alarmins and Antitumor Immunity.
Clinical therapeutics, 2016Co-Authors: Yingjie Nie, De Yang, Joost J OppenheimAbstract:Abstract 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.
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Harnessing the Alarmin HMGN1 for anticancer therapy.
Immunotherapy, 2015Co-Authors: De Yang, Michael Bustin, Joost J OppenheimAbstract:Incipient cancer cells formed as a result of mutations of oncogene(s), tumor suppressor gene(s) and/or DNA repair gene(s) develop into malignant tumors depending on three processes. They acquire a higher rate of mutation due to increased sensitivity to endogenous and exogenous mutagenic agents or due to a breakdown in one or several components of the DNA repair machinery [1]. They need to be induced to grow by hormones, cytokines and other mitogenic signals and achieve replicative immortality. Finally, the host’s immunosurveillance function fails because of immunoediting [2] and formation of an immunossupressive tumor microenvironment, resulting in preventing the immune control or rejection of the cancers [1,2]. Reagents that interfere with any of these processes have been identified as potential anticancer therapeutics [1]. We have shown the high mobility group nucleosome-binding protein 1 (HMGN1) to have a combination of activities that potentially counters the mutagenic and immunosuppressive properties of cancers. HMGN1 is a chromatin-binding nuclear protein and that can act as an extracellular Alarmin. In this respect, HMGN1 is similar to the well known Alarmin, HMGB1. Although HMGN1 and HMGB1 function both as chromatin binding proteins and as Alarmins, they are otherwise completely distinct proteins, unrelated in amino acid sequence. Two biological activities of HMGN1 can potentially be harnessed as antitumor activities. First, inside the nucleus, HMGN1 acts as a chromatin modifier to regulate chromatin structure, gene expression and post-translational modification of core histones, all of which are factors that affect DNA repair and tumor progression [3]. Second, HMGN1 is released by nonleukocytes such as epithelial cells in response to injurious agents, changes in intracellular calcium and inflammatory stimulants. When released by the cells, extracellular HMGN1 function as a Th1-polarizing Alarmin that promotes the induction of innate and adaptive antitumor immune responses [4]. In the absence of nuclear HMGN1, cells become prone to mutagenic stimuli. Hmgn1 cells derived from HMGN1 knockout mice are hypersensitive to UV and ionizing irradiation, and show decreased capacity to repair DNA damage [5,6]. Consequently, Hmgn1 mice exhibit increased tumor formation in response to irradiation [7] or chemical carcinogens [8]. Even without treatment with exogenous DNA-damaging agents, Hmgn1 mice develop twice as many spontaneous tumors as their Hmgn1 littermates [7], supporting the notion that HMGN1 plays a role in DNA repair and the maintenance of genome stability. Given the requirement of multiple mutations in the course of cancer development [1,9], HMGN1 could potentially be used as a molecular target designed to counteract Harnessing the Alarmin HMGN1 for anticancer therapy
André Herbelin – One of the best experts on this subject based on the ideXlab platform.
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The Impact of Invariant NKT Cells in Sterile Inflammation: The Possible Contribution of the Alarmin/Cytokine IL-33
Frontiers in Immunology, 2018Co-Authors: Maroua Haroun Ferhat, Aurélie Robin, Louise Barbier, Antoine Thierry, Jean-marc Gombert, Alice Barbarin, André HerbelinAbstract:Although the contribution of iNKT cells to induction of sterile inflammation is now well-established, the nature of the endogenous compounds released early after cellular stress or damage that drive their activation and recruitment remains poorly understood. More precisely, iNKT cells have not been described as being reactive to endogenous non-protein damage-associated molecular-pattern molecules (DAMPs). A second subset of DAMPs, called Alarmins, are tissue-derived nuclear proteins, constitutively expressed at high levels in epithelial barrier tissues and endothelial barriers. These potent immunostimulants, immediately released after tissue damage, include the Alarmin IL-33. This factor has aroused interest due to its singular action as an Alarmin during infectious, allergic responses and acute tissue injury, and as a cytokine, contributing to the latter resolutive/repair phase of sterile inflammation. IL-33 targets iNKT cells, inducing their recruitment in an inflammatory state, and amplifying their regulatory and effector functions. In the present review, we introduce the new concept of a biological axis of iNKT cells and IL-33, involved in alerting and controlling the immune cells in experimental models of sterile inflammation. This review will focus on acute organ injury models, especially ischemia-reperfusion injury, in the kidneys, liver and lungs, where iNKT cells and IL-33 have been presumed to mediate and/or control the injury mechanisms, and their potential relevance in human pathophysiology.
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the impact of invariant nkt cells in sterile inflammation the possible contribution of the Alarmin cytokine il 33
Frontiers in Immunology, 2018Co-Authors: Maroua Haroun Ferhat, Aurélie Robin, Louise Barbier, Antoine Thierry, Jean-marc Gombert, Alice Barbarin, André HerbelinAbstract:Although the contribution of iNKT cells to induction of sterile inflammation is now well-established, the nature of the endogenous compounds released early after cellular stress or damage that drive their activation and recruitment remains poorly understood. More precisely, iNKT cells have not been described as being reactive to endogenous non-protein damage-associated molecular-pattern molecules (DAMPs). A second subset of DAMPs, called Alarmins, are tissue-derived nuclear proteins, constitutively expressed at high levels in epithelial barrier tissues and endothelial barriers. These potent immunostimulants, immediately released after tissue damage, include the Alarmin IL-33. This factor has aroused interest due to its singular action as an Alarmin during infectious, allergic responses and acute tissue injury, and as a cytokine, contributing to the latter resolutive/repair phase of sterile inflammation. IL-33 targets iNKT cells, inducing their recruitment in an inflammatory state, and amplifying their regulatory and effector functions. In the present review, we introduce the new concept of a biological axis of iNKT cells and IL-33, involved in alerting and controlling the immune cells in experimental models of sterile inflammation. This review will focus on acute organ injury models, especially ischemia-reperfusion injury, in the kidneys, liver and lungs, where iNKT cells and IL-33 have been presumed to mediate and/or control the injury mechanisms, and their potential relevance in human pathophysiology.
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IL-33 receptor ST2 deficiency attenuates renal ischaemia–reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice
Journal of Diabetes & Metabolism, 2018Co-Authors: M. Sehnine, Maroua Haroun Ferhat, André Herbelin, M. Ferhat, S. Sena, J.m. Gombert, J.m. Goujon, A. Thierry, G. Touchard, T. Hauet, Samy HadjadjAbstract:AIM: Kidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia-reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas Alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2-/-) on renal IRI in euglycaemic and hyperglycaemic mice. METHODS: Hyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2-/- mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal arteartery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. RESULTS: Urinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2-/- mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2-/- animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. CONCLUSION: Our data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening-up new avenues for future research on Alarmins and diabetes in ischaemia-related diseases.
Axel M. Küchler – One of the best experts on this subject based on the ideXlab platform.
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interleukin 33 cytokine of dual function or novel Alarmin
Trends in Immunology, 2009Co-Authors: Guttorm Haraldsen, Axel M. Küchler, Johanna Balogh, Jürgen Pollheimer, Jon SponheimAbstract:Cytokines are thought to exert biological effects through their specific cell surface membrane receptors but increasing evidence suggests that some also function within the nucleus. Here, we review current knowledge of such cytokines, including the novel interleukin (IL)-1 family member IL-33. Its extracellular function has attracted much recent attention as a ligand for the Th2-associated ST2 receptor, but the discoveries of its nuclear functions and modes of secretion are only just beginning to surface. We review the currently available data on IL-33 regulation, nuclear function and release and discuss them in the context of other intranuclear cytokines and the prototype Alarmin HMGB1, considering to what extent IL-33 can be seen as a novel member of the Alarmin family.
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Interleukin-33 – cytokine of dual function or novel Alarmin?
Trends in immunology, 2009Co-Authors: Guttorm Haraldsen, Johanna Balogh, Jürgen Pollheimer, Jon Sponheim, Axel M. KüchlerAbstract:Cytokines are thought to exert biological effects through their specific cell surface membrane receptors but increasing evidence suggests that some also function within the nucleus. Here, we review current knowledge of such cytokines, including the novel interleukin (IL)-1 family member IL-33. Its extracellular function has attracted much recent attention as a ligand for the Th2-associated ST2 receptor, but the discoveries of its nuclear functions and modes of secretion are only just beginning to surface. We review the currently available data on IL-33 regulation, nuclear function and release and discuss them in the context of other intranuclear cytokines and the prototype Alarmin HMGB1, considering to what extent IL-33 can be seen as a novel member of the Alarmin family.
Helena Erlandsson Harris – One of the best experts on this subject based on the ideXlab platform.
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High-mobility group box 1 protein (HMGB1) operates as an Alarmin outside as well as inside cells
Seminars in immunology, 2018Co-Authors: Ulf Andersson, Huan Yang, Helena Erlandsson HarrisAbstract:Alarmins are preformed, endogenous molecules that can be promptly released to signal cell or tissue stress or damage. The ubiquitous nuclear molecule high-mobility group box 1 protein (HMGB1) is a prototypical Alarmin activating innate immunity. HMGB1 serves a dual Alarmin function. The protein can be emitted to alert adjacent cells about endangered homeostasis of the HMGB1-releasing cell. In addition to this expected path of an Alarmin, extracellular HMGB1 can be internalized via RAGE-receptor mediated endocytosis to the endolysosomal compartment while attached to other extracellular proinflammatory molecules. The endocytosed HMGB1 may subsequently destabilize lysosomal membranes. The HMGB1-bound partner molecules depend on the HMGB1-mediated transport and the induced lysosomal leakage to obtain access to endosomal and cytosolic reciprocal sensors to communicate extracellular threat and to initiate the proper activation pathways.
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hmgb1 a multifunctional Alarmin driving autoimmune and inflammatory disease
Nature Reviews Rheumatology, 2012Co-Authors: Helena Erlandsson Harris, Ulf Andersson, David S PisetskyAbstract:HMGB1 is a non-histone nuclear protein that can serve as an Alarmin to drive the pathogenesis of inflammatory and autoimmune disease. Although primarily located in the cell nucleus, HMGB1 can translocate to the cytoplasm, as well as the extracellular space, during cell activation and cell death; during activation, HMGB1 can undergo post-translational modifications. The activity of HMGB1 varies with the redox states of the cysteine residues, which are required for binding to TLR4. In addition to stimulating cells directly, HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous factors. In the synovia of patients with rheumatoid arthritis, as well as animal models of this disease, extranuclear expression of HMGB1 is increased and blockade of HMGB1 expression attenuates disease in animal models. In systemic lupus erythematosus, HMGB1 can be a component of immune complexes containing anti-DNA because of its interaction with DNA. In myositis, expression of HMGB1 is enhanced in inflamed muscle and can perturb muscle function. Together, these findings indicate that HMGB1 might be an important mediator and biomarker in rheumatic diseases as well as a target of new therapy.
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Alarmin(g) news about danger: workshop on innate danger signals and HMGB1.
EMBO reports, 2006Co-Authors: Helena Erlandsson Harris, Angela RaucciAbstract:The EMBO Workshop on Innate Danger Signals and HMGB1 took place between 8 and 11 February 2006 in Milan, Italy, and was organized by M. Bianchi, K. Tracey and U. Andersson. ![][1] During evolution, multicellular organisms have developed mechanisms to counteract life‐threatening events, such as infections and tissue injury, as well as to restore tissue homehomeostasis. These mechanisms are called ‘the inflammatory response‘. To initiate an appropriate inflammatory response, organisms have developed ways to recognize potentially life‐threatening events. Danger signals—the molecules that alert the innate immuimmune system and trigger defensive immune responses—have been classically defined as exogenous, pathogen‐associated molecular pattern (PAMP) molecules. PAMPs—for example, lipopolysacharide (LPS), viral RNA and bacterial petidoglycans—interact with dedicated receptors on immune cells, the so‐called pattern recognition receptors (PRRs). On ligation, PRRs transduce activation signals that lead to the production of proinflammatory molecules such as tumour necrosis factor (TNF). A well‐known family of PRRs is the toll‐like receptor (TLR) family in which each member recognizes a specific set of PAMPs. However, several endogenous molecules also initiate inflammatory responses by interacting with signalling receptors; such innate danger signals are known as endokines and/or Alarmins. The term endokine reflects the potential of these molecules with intranuclear and/or intracellular functions also to act extracellularly, in this case to be immunostimulatory on their release from necrotic cells. The endokine family includes high‐mobility‐group box (HMGB) proteins, interleukins such as IL‐1α, cytosolic calcium‐binding protproteins of the S100 family, heat‐shock proteins (HSPs) and nucleosomes. The term Alarmin, coined by J. Oppenheim (Frederick, MD, USA) and co‐workers, denotes an array of structurally diverse multifunctional host proteins that are rapidly released during infection or tissue damage, and that have mobilizing and activating effects on receptor‐expressing cells engaged in host defence and tissue repair. Innate‐immune mediators that have Alarmin function include defensins, eosinophil‐derived neurotoxin, cathelicidins and HMGB1 … [1]: /embed/graphic-1.gif