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European Respiratory Review : An... Mar 2023Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette... (Review)
Review
Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments. The epithelial cytokines/alarmins are involved in exacerbations; biologics targeting TSLP and IL-33 have been shown to reduce exacerbations in moderate-to-severe asthma, either in a broad population or in specific subgroups, respectively. For COPD, while there is clinical evidence for IL-33 blockade impacting exacerbations in COPD, clinical data from anti-TSLP therapies is awaited. Clinical data to date support an acceptable safety profile for patients with airway diseases for both anti-IL-33 and anti-TSLP antibodies in development. We examine the roles of IL-33 and TSLP, their potential use as drug targets, and the evidence for target patient populations for COPD and asthma, together with ongoing and future trials focused on these targets.
Topics: Humans; Thymic Stromal Lymphopoietin; Immunity, Innate; Interleukin-33; Alarmins; Lymphocytes; Cytokines; Asthma; Inflammation; Lung; Pulmonary Disease, Chronic Obstructive
PubMed: 36697211
DOI: 10.1183/16000617.0144-2022 -
Cells Aug 2019Located at the skin surface, keratinocytes (KCs) are constantly exposed to external stimuli and are the first responders to invading pathogens and injury. Upon skin... (Review)
Review
Located at the skin surface, keratinocytes (KCs) are constantly exposed to external stimuli and are the first responders to invading pathogens and injury. Upon skin injury, activated KCs secrete an array of alarmin molecules, providing a rapid and specific innate immune response against danger signals. However, dysregulation of the innate immune response of KCs may lead to uncontrolled inflammation and psoriasis pathogenesis. Keratins (KRT) are the major structural intermediate filament proteins in KCs and are expressed in a highly specific pattern at different differentiation stages of KCs. While KRT14-KRT5 is restricted to basal proliferative KCs, and KRT10-KRT1 is restricted to suprabasal differentiated KCs in normal skin epidermis, the wound proximal KCs downregulate KRT10-K1 and upregulate KRT16/KRT17-KRT6 upon skin injury. Recent studies have recognized KRT6/16/17 as key early barrier alarmins and upregulation of these keratins alters proliferation, cell adhesion, migration and inflammatory features of KCs, contributing to hyperproliferation and innate immune activation of KCs in response to an epidermal barrier breach, followed by the autoimmune activation of T cells that drives psoriasis. Here, we have reviewed how keratins are dysregulated during skin injury, their roles in wound repairs and in initiating the innate immune system and the subsequent autoimmune amplification that arises in psoriasis.
Topics: Alarmins; Cell Adhesion; Cell Differentiation; Cell Movement; Cell Proliferation; Gene Expression Regulation; Humans; Immunity, Innate; Keratin-16; Keratin-17; Keratin-6; Psoriasis; Wound Healing
PubMed: 31374826
DOI: 10.3390/cells8080807 -
The European Respiratory Journal Nov 2020Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available... (Review)
Review
Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig)E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2-low asthma. Existing biologics target immunological pathways that are downstream in the type 2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, type 2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide ( ), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of "alarmins" thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with type 2-high and type 2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.
Topics: Alarmins; Asthma; Biological Products; Cytokines; Eosinophils; Epithelium; Humans
PubMed: 32586879
DOI: 10.1183/13993003.00260-2020 -
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 -
International Journal of Molecular... Aug 2021Sepsis is characterized by a dysregulated immune response to infections that causes life-threatening organ dysfunction and even death. When infections occur, bacterial... (Review)
Review
Sepsis is characterized by a dysregulated immune response to infections that causes life-threatening organ dysfunction and even death. When infections occur, bacterial cell wall components (endotoxin or lipopolysaccharide), known as pathogen-associated molecular patterns, bind to pattern recognition receptors, such as toll-like receptors, to initiate an inflammatory response for pathogen elimination. However, strong activation of the immune system leads to cellular dysfunction and ultimately organ failure. Damage-associated molecular patterns (DAMPs), which are released by injured host cells, are well-recognized triggers that result in the elevation of inflammatory cytokine levels. A cytokine storm is thus amplified and sustained in this vicious cycle. Interestingly, during sepsis, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. Thus, the concept of blood purification has evolved to include inflammatory cells and mediators. In this review, we summarize recent advances in knowledge regarding the role of lipopolysaccharides, cytokines, DAMPs, and neutrophils in the pathogenesis of sepsis. Additionally, we discuss the potential of blood purification, especially the adsorption technology, for removing immune cells and molecular mediators, thereby serving as a therapeutic strategy against sepsis. Finally, we describe the concept of our immune-modulating blood purification system.
Topics: Alarmins; Animals; Cytokine Release Syndrome; Humans; Immunity, Innate; Pathogen-Associated Molecular Pattern Molecules; Plasma Exchange; Sepsis
PubMed: 34445610
DOI: 10.3390/ijms22168882 -
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 -
Nature Communications Oct 2022Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin...
Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.
Topics: Alarmins; Animals; Astrocytes; Culture Media, Conditioned; Endothelial Cells; Endothelium; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Reactive Oxygen Species; Spinal Cord; Spinal Cord Injuries
PubMed: 36184639
DOI: 10.1038/s41467-022-33463-x -
Immunity Apr 2023T cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and...
T cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8 T cells (CD8SL) remain poorly defined. Studying CD8 T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8 T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8SL-promoting pathway in the context of chronic viral infection.
Topics: Animals; Mice; Alarmins; CD8-Positive T-Lymphocytes; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice, Inbred C57BL; Persistent Infection; T Cell Transcription Factor 1
PubMed: 36809763
DOI: 10.1016/j.immuni.2023.01.029 -
Immunity Apr 2022The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines,...
The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.
Topics: Acylation; Alarmins; Anthelmintics; Biomarkers, Tumor; Cytokines; DNA-Binding Proteins; Helminthiasis; Humans; Hyperplasia; Inflammation; Interleukin-33; Intestinal Mucosa; Mebendazole; N-Acetylglucosaminyltransferases; Pore Forming Cytotoxic Proteins; STAT6 Transcription Factor
PubMed: 35385697
DOI: 10.1016/j.immuni.2022.03.009 -
Frontiers in Immunology 2021
Topics: Alarmins; Animals; Disease Susceptibility; Homeostasis; Host-Pathogen Interactions; Humans; Immunity; Plant Diseases; Plant Physiological Phenomena
PubMed: 35178047
DOI: 10.3389/fimmu.2021.844315