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Allergy Feb 2023The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and... (Review)
Review
The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.
Topics: Humans; Cytokines; Alarmins; Interleukin-33; Interleukin-1 Receptor-Like 1 Protein; Asthma; Thymic Stromal Lymphopoietin; Inflammation
PubMed: 36463491
DOI: 10.1111/all.15609 -
Cell Stem Cell Apr 2021Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs)...
Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
Topics: Alarmins; Animals; Bone Marrow; Humans; Mesenchymal Stem Cells; Mice; Myeloproliferative Disorders; Primary Myelofibrosis
PubMed: 33301706
DOI: 10.1016/j.stem.2020.11.004 -
Frontiers in Immunology 2022The exposure of the airway epithelium to external stimuli such as allergens, microbes, and air pollution triggers the release of the alarmin cytokines IL-25, IL-33 and... (Review)
Review
The exposure of the airway epithelium to external stimuli such as allergens, microbes, and air pollution triggers the release of the alarmin cytokines IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). IL-25, IL-33 and TSLP interact with their ligands, IL-17RA, IL1RL1 and TSLPR respectively, expressed by hematopoietic and non-hematopoietic cells including dendritic cells, ILC2 cells, endothelial cells, and fibroblasts. Alarmins play key roles in driving type 2-high, and to a lesser extent type 2-low responses, in asthma. In addition, studies in which each of these three alarmins were targeted in allergen-challenged mice showed decreased chronicity of type-2 driven disease. Consequently, ascertaining the mechanism of activity of these upstream mediators has implications for understanding the outcome of targeted therapies designed to counteract their activity and alleviate downstream type 2-high and low effector responses. Furthermore, identifying the factors which shift the balance between the elicitation of type 2-high, eosinophilic asthma and type-2 low, neutrophilic-positive/negative asthma by alarmins is essential. In support of these efforts, observations from the NAVIGATOR trial imply that targeting TSLP in patients with tezepelumab results in reduced asthma exacerbations, improved lung function and control of the disease. In this review, we will discuss the mechanisms surrounding the secretion of IL-25, IL-33, and TSLP from the airway epithelium and how this influences the allergic airway cascade. We also review in detail how alarmin-receptor/co-receptor interactions modulate downstream allergic inflammation. Current strategies which target alarmins, their efficacy and inflammatory phenotype will be discussed.
Topics: Mice; Animals; Alarmins; Interleukin-33; Immunity, Innate; Endothelial Cells; Lymphocytes; Asthma; Cytokines; Allergens; Epithelial Cells; Interleukin-1 Receptor-Like 1 Protein
PubMed: 36311787
DOI: 10.3389/fimmu.2022.975914 -
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 -
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 -
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 -
Current Opinion in Pulmonary Medicine Jan 2020The alarmins, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, are upstream regulators of T2 (type 2) inflammation and found to be expressed at high... (Review)
Review
PURPOSE OF REVIEW
The alarmins, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, are upstream regulators of T2 (type 2) inflammation and found to be expressed at high levels in airway epithelium of patients with T2 asthma. This review will summarize how alarmins regulate the inflamed asthmatic airways through previously described and newly identified mechanisms.
RECENT FINDINGS
Alarmins drive allergic and nonallergic asthma through activation of innate lymphoid cell 2 (ILC2), which are a rich source of cytokines such as IL-5 and IL-13, with resulting effects on eosinophilopoeisis and remodelling, respectively. Findings from bronchial allergen challenges have illustrated widespread expression of alarmins and their receptors across many effector cells in airways, and recent studies have emphasized alarmin regulation of CD4 T lymphocytes, eosinophils and basophils, and their progenitors. Furthermore, a link between alarmins and lipid mediators is being uncovered.
SUMMARY
Alarmins can drive well defined inflammatory pathways through activation of dendritic cells and polarizing T cells to produce type 2 cytokines, as well as they can directly activate many other effector cells that play a central role in allergic and nonallergic asthma. Clinical trials support a central role for TSLP in driving airway inflammation and asthma exacerbations, while ongoing trials blocking IL-33 and IL-25 will help to define their respective role in asthma.
Topics: Alarmins; Animals; Asthma; Drug Discovery; Humans; Immunity, Innate; Respiratory Mucosa
PubMed: 31408015
DOI: 10.1097/MCP.0000000000000615 -
Cell Host & Microbe Feb 2021The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2-infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.
Topics: Alarmins; Animals; Antiviral Agents; COVID-19; Disease Models, Animal; Female; Humans; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; SARS-CoV-2; Transcriptome; Viral Load; COVID-19 Drug Treatment
PubMed: 33388094
DOI: 10.1016/j.chom.2020.12.016 -
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 -
American Journal of Physiology. Cell... Nov 2023Environmental allergens that interact with the airway epithelium can activate cellular stress pathways that lead to the release of danger signals known as alarmins. The... (Review)
Review
Environmental allergens that interact with the airway epithelium can activate cellular stress pathways that lead to the release of danger signals known as alarmins. The mechanisms of alarmin release are distinct from damage-associated molecular patterns (DAMPs), which typically escape from cells after loss of plasma membrane integrity. Oxidative stress represents a form of allergen-induced cellular stress that stimulates oxidant-sensing mechanisms coupled to pathways, which facilitate alarmin mobilization and efflux across the plasma membrane. In this review, we highlight examples of alarmin release and discuss their roles in the initiation of type 2 immunity and allergic airway inflammation. In addition, we discuss the concept of alarmin amplification, where "primary" alarmins, which are directly released in response to a specific cellular stress, stimulate additional signaling pathways that lead to secretion of "secondary" alarmins that include proinflammatory cytokines, such as IL-33, as well as genomic and mitochondrial DNA that coordinate or amplify type 2 immunity. Accordingly, allergen-evoked cellular stress can elicit a hierarchy of alarmin signaling responses from the airway epithelium that trigger local innate immune reactions, impact adaptive immunity, and exacerbate diseases including asthma and other chronic inflammatory conditions that affect airway function.
Topics: Humans; Allergens; Alarmins; Cytokines; Asthma; Inflammation; Adenosine Triphosphate; Immunity, Innate
PubMed: 37842751
DOI: 10.1152/ajpcell.00370.2023