-
Brain, Behavior, and Immunity Aug 2015High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and... (Review)
Review
High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and pro-inflammatory cytokine release. HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including ischemia, traumatic brain injury, seizure and chronic ethanol use. In the present review, the unique structural and functional properties of HMGB1 will be explored including its affinity for multiple pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein glucocorticoids induce synthesis and release of HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3 inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an alarmin by inducing HMGB1, thereby preparing an organism's innate immune system (NLRP3 inflammasome priming) for subsequent immune challenges such as injury, trauma or infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges.
Topics: Alarmins; Animals; Brain; HMGB1 Protein; Immunity, Innate; Inflammasomes; Inflammation; Stress, Physiological
PubMed: 25816800
DOI: 10.1016/j.bbi.2015.03.010 -
Journal of Thrombosis and Haemostasis :... Feb 2018The inflammatory response and the activation of coagulation are two important responses in a host's defense against infection. These mechanisms do not work... (Review)
Review
The inflammatory response and the activation of coagulation are two important responses in a host's defense against infection. These mechanisms do not work independently, but cooperate in a complex and synchronous manner. Recent research has also shed light on the critical role of thrombus formation, which prevents the dissemination of microorganisms. The cellular components of blood vessels, i.e. leukocytes, platelets, erythrocytes, and vascular endothelial cells, play significant roles in the development of thrombi in combination with activation of the coagulation system. In addition to the cellular components, alarmins such as histones and high-mobility group box 1, microparticles and secreted granule proteins are all important for clot formation. In this summary, we review the pathophysiology of sepsis-induced coagulopathy and the role of cellular components and critical factors released from damaged cells. In addition, we review important therapeutic approaches that have been developed, are under investigation and are currently available in certain countries, including antithrombin, recombinant thrombomodulin, anti-Toll-like receptor 4 therapy, anti-damage associated molecular pattern therapy, and hemoadsorption with a polymyxin B-immobilized fiber column.
Topics: Alarmins; Animals; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Blood Platelets; Cell Communication; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Neutrophils; Platelet Aggregation Inhibitors; Sepsis; Signal Transduction; Thrombosis
PubMed: 29193703
DOI: 10.1111/jth.13911 -
Molecular Human Reproduction Sep 2020Sterile intra-amniotic inflammation is a clinical condition frequently observed in women with preterm labor and birth, the leading cause of neonatal morbidity and...
Sterile intra-amniotic inflammation is a clinical condition frequently observed in women with preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Growing evidence suggests that alarmins found in amniotic fluid, such as interleukin (IL)-1α, are central initiators of sterile intra-amniotic inflammation. However, the causal link between elevated intra-amniotic concentrations of IL-1α and preterm birth has yet to be established. Herein, using an animal model of ultrasound-guided intra-amniotic injection of IL-1α, we show that elevated concentrations of IL-1α cause preterm birth and neonatal mortality. Additionally, using immunoblotting techniques and a specific immunoassay, we report that the intra-amniotic administration of IL-1α induces activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the fetal membranes, but not in the decidua, as evidenced by a concomitant increase in the protein levels of NLRP3, active caspase-1, and IL-1β. Lastly, using Nlrp3-/- mice, we demonstrate that the deficiency of this inflammasome sensor molecule reduces the rates of preterm birth and neonatal mortality caused by the intra-amniotic injection of IL-1α. Collectively, these results demonstrate a causal link between elevated IL-1α concentrations in the amniotic cavity and preterm birth as well as adverse neonatal outcomes, a pathological process that is mediated by the NLRP3 inflammasome. These findings shed light on the mechanisms underlying sterile intra-amniotic inflammation and provide further evidence that this clinical condition can potentially be treated by targeting the NLRP3 inflammasome.
Topics: Alarmins; Amniotic Fluid; Animals; Animals, Newborn; Female; Inflammasomes; Interleukin-1alpha; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NLR Family, Pyrin Domain-Containing 3 Protein; Pregnancy; Premature Birth
PubMed: 32647859
DOI: 10.1093/molehr/gaaa054 -
Journal of Experimental & Clinical... Oct 2023Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor...
BACKGROUND
Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70).
METHODS
Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes.
RESULTS
It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models.
CONCLUSIONS
These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.
Topics: Humans; HSP70 Heat-Shock Proteins; Alarmins; HMGB1 Protein; Culture Media, Conditioned; Proteomics; Chronic Disease; Recurrence; Prostaglandins
PubMed: 37880798
DOI: 10.1186/s13046-023-02857-0 -
Nature Communications May 2021Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages...
Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.
Topics: Alarmins; Animals; Antigen Presentation; Antigens, Neoplasm; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Immunotherapy; Male; Mice; Mice, Knockout; Neoplasms; Proof of Concept Study; Radiation Tolerance; Receptors, Immunologic; T-Lymphocytes, Cytotoxic; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 34050181
DOI: 10.1038/s41467-021-23442-z -
Frontiers in Immunology 2021
Topics: Alarmins; Anemia, Hemolytic; Animals; Biomarkers; Disease Susceptibility; Erythrocytes; Genetic Predisposition to Disease; Hemolysis; Humans; Inflammation; Inflammation Mediators
PubMed: 35095935
DOI: 10.3389/fimmu.2021.834527 -
Archives of Cardiovascular Diseases 2021
Topics: Alarmins; Humans; Myocardial Infarction; Myocardium; S100 Calcium Binding Protein beta Subunit
PubMed: 34119439
DOI: 10.1016/j.acvd.2021.04.006 -
Current Opinion in Organ Transplantation Feb 2016The purpose of this review is to provide a general update on recent developments in the immunobiology of IL-33 and IL-33-targeted immune cells. We also discuss emerging... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide a general update on recent developments in the immunobiology of IL-33 and IL-33-targeted immune cells. We also discuss emerging concepts regarding the potential role IL-33 appears to play in altering alloimmune responses mediating host-versus-graft and graft-versus-host alloresponses.
RECENT FINDINGS
Stromal cells and leukocytes display regulated expression of IL-33 and may actively or passively secrete this pleotropic cytokine. Type 2 innate lymphoid cells and a large proportion of tissue resident regulatory T cells (Treg) express membrane-bound suppressor of tumorigenicity 2 (ST2), the IL-33 receptor. Although Treg are appreciated suppressors of the inflammatory function of immune cells, both type 2 innate lymphoid cells and tissue resident Treg could play key roles in tissue repair and homeostasis. The functions of IL-33 in transplantation are poorly understood. However, like other disease models, the functions of IL-33 in alloimmunity appear to be quite pleiotropic. IL-33 is associated with immune regulation and graft protection in cardiac transplant settings. Yet, it is highly proinflammatory and stimulates lethal graft-versus-host disease through its capacity to stimulate type 1 immunity.
SUMMARY
Intensive studies on IL-33/ST2 signaling pathways and ST2 cell populations in solid organ and cell transplantation are warranted. A better understanding of this important pathway will provide promising therapeutic targets controlling pathogenic alloimmune responses, as well as potentially facilitating the function of regulatory and reparative immune cells posttransplantation.
Topics: Alarmins; Animals; Graft vs Host Disease; Humans; Interleukin-33; Lymphocytes; Signal Transduction
PubMed: 26709577
DOI: 10.1097/MOT.0000000000000265 -
Mucosal Immunology Oct 2023Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context...
Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1), and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterised by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis and produced greater amounts of IL-1α/β, IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.
Topics: Humans; Animals; Mice; Rhinovirus; Interleukin-33; Interleukin-4; Alarmins; Asthma; Inflammation; Neutrophils; Extracellular Traps
PubMed: 37506849
DOI: 10.1016/j.mucimm.2023.07.002 -
Nature Reviews. Immunology May 2018
Topics: Alarmins; Allergens; Humans; Hypersensitivity; Inflammation; Interleukin-33
PubMed: 29616684
DOI: 10.1038/nri.2018.23