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Nature Immunology Jan 2020
Topics: Alarmins; Apolipoprotein C-III; Humans; Inflammasomes; Inflammation
PubMed: 31822868
DOI: 10.1038/s41590-019-0562-3 -
Clinical and Translational Medicine Apr 2023Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the...
BACKGROUND
Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS.
METHODS
Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS.
RESULTS
We provide evidence that loss of Ca signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca homeostasis that inhibited alarmin release thereby reverting the pSS phenotype.
CONCLUSIONS
These results indicate that loss of Ca signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.
Topics: Humans; Animals; Mice; Sjogren's Syndrome; Alarmins; Salivary Glands; Saliva; Phenotype
PubMed: 37006181
DOI: 10.1002/ctm2.1228 -
European Journal of Immunology Apr 2023Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air-liquid interface (ALI) epithelial...
Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air-liquid interface (ALI) epithelial cultures and whether this local orientation can be related to systemic patterns (e.g., blood eosinophil counts [BECs]). We investigated alarmin release related to high versus low T2 phenotypes associated with chronic airway diseases. ALIs were reconstituted from 32 control, 40 chronic obstructive pulmonary disease, and 20 asthmatic patients. Interleukin-8 (IL-8; a T1-cytokine), IL-25, IL-33, and thymic stromal lymphopoietin (T2-alarmins) concentrations were assessed in subnatants at steady state and used to explain blood neutrophil and eosinophil counts. IL-25 and IL-8 levels were highest in asthma ALI-subnatants, whereas IL-33 was sparsely detected. Thymic stromal lymphopoietin levels were similar among groups. All asthma cell cultures were T1-high/T2-high, while chronic obstructive pulmonary disease and controls tended to be mixed. BECs were independently explained by both disease and in-culture T2-alarmin levels, irrespective of the T2-alarmin considered. The epithelial ALI-T2 signature was more frequently high in patients with a BEC > 300/mm . Despite removal from an in vivo environment for ≥2 months, ALIs release disease-specific cytokine "cocktails" into their subnatants, suggesting continued persistence of alarmin orientation in differentiated cell line environments.
Topics: Humans; Alarmins; Interleukin-33; Eosinophils; Interleukin-8; Cytokines; Asthma; Thymic Stromal Lymphopoietin; Pulmonary Disease, Chronic Obstructive
PubMed: 36793156
DOI: 10.1002/eji.202250101 -
Arteriosclerosis, Thrombosis, and... Aug 2020
Topics: Alarmins; Diabetes Mellitus; Extracellular Vesicles; Humans; Inflammation; Macrophages; Oxidation-Reduction
PubMed: 32697681
DOI: 10.1161/ATVBAHA.120.314733 -
Molecular and Cellular Endocrinology Oct 2017Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent... (Review)
Review
Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent and low-grade inflammation in the adipose tissue, and serves as an independent risk factor for many metabolic disorders such as diabetes and cardiovascular disease. Particularly, adipocytes originated from obese mice and humans likely predominate necrosis upon stressful insults, leading to passive release of cellular contents including the high mobility group box 1 (HMGB1) into the extracellular milieu. Extracellular HMGB1 acts as an innate alarmin to stimulate the activation of resident immune cells in the adipose tissue. Upon activation, those resident immune cells actively secrete additional HMGB1, which in turn activates/recruits additional immune cells, and induces adipocyte death. This review summarizes those novel discoveries in terms of HMGB1 in the initiation and maintenance of chronic inflammatory state in adipose tissue in obesity, and discusses its potential application in clinical settings.
Topics: Adipose Tissue; Alarmins; Animals; Chronic Disease; HMGB1 Protein; Humans; Inflammation; Obesity
PubMed: 28619625
DOI: 10.1016/j.mce.2017.06.012 -
Nature Reviews. Gastroenterology &... Jan 2016IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's... (Review)
Review
IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.
Topics: Adaptive Immunity; Adult; Alarmins; Causality; Child; Colitis, Ulcerative; Crohn Disease; Cultural Evolution; Gene Expression Regulation; Humans; Immunity, Innate; Inflammasomes; MicroRNAs; Microbiota; Regulatory Sequences, Ribonucleic Acid
PubMed: 26627550
DOI: 10.1038/nrgastro.2015.186 -
Seminars in Immunology Aug 2018High-mobility group (HMG) nucleosome binding domain 1 (HMGN1), which previously was thought to function only as a nucleosome-binding protein that regulates chromatin... (Review)
Review
High-mobility group (HMG) nucleosome binding domain 1 (HMGN1), which previously was thought to function only as a nucleosome-binding protein that regulates chromatin structure, histone modifications, and gene expression, was recently discovered to be an alarmin that contributes extracellularly to the generation of innate and adaptive immune responses. HMGN1 promotes DC recruitment through interacting with a Gαi protein-coupled receptor (GiPCR) and activates DCs predominantly through triggering TLR4. HMGN1 preferentially promotes Th1-type immunity, which makes it relevant for the fields of vaccinology, autoimmunity, and oncoimmunology. Here, we discuss the alarmin properties of HMGN1 and update recent advances on its roles in immunity and potential applications for immunotherapy of tumors.
Topics: Alarmins; Dendritic Cells; HMGN1 Protein; Humans; Immunity; Neoplasms; Signal Transduction; Th1 Cells
PubMed: 29503123
DOI: 10.1016/j.smim.2018.02.012 -
Nature Reviews. Immunology Jun 2017Mitochondrial DNA (mtDNA) - which is well known for its role in oxidative phosphorylation and maternally inherited mitochondrial diseases - is increasingly recognized as... (Review)
Review
Mitochondrial DNA (mtDNA) - which is well known for its role in oxidative phosphorylation and maternally inherited mitochondrial diseases - is increasingly recognized as an agonist of the innate immune system that influences antimicrobial responses and inflammatory pathology. On entering the cytoplasm, extracellular space or circulation, mtDNA can engage multiple pattern-recognition receptors in cell-type- and context-dependent manners to trigger pro-inflammatory and type I interferon responses. Here, we review the expanding research field of mtDNA in innate immune responses to highlight new mechanistic insights and discuss the physiological and pathological relevance of this exciting area of mitochondrial biology.
Topics: Alarmins; Animals; DNA, Mitochondrial; Humans; Immunity, Innate; Inflammation
PubMed: 28393922
DOI: 10.1038/nri.2017.21 -
The Journal of Experimental Medicine Jun 2024Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here,...
Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low "ILC9" phenotype and produce prodigious amounts of IL-9. A combination of large-scale proteomic analyses, lung intravital microscopy, and adoptive transfer of ILC9 cells revealed that high IL-9 expression distinguishes a multicytokine-producing state-of-activated ILC2s with an increased capacity to initiate IL-5-dependent allergic airway inflammation. Similar to IL-33 and TSLP, TL1A is expressed in airway basal cells in healthy and asthmatic human lungs. Together, these results indicate that TL1A is an epithelium-derived cytokine and an important cofactor of IL-33 in the airways.
Topics: Animals; Humans; Mice; Alarmins; Asthma; Cytokines; Immunity, Innate; Inflammation; Interleukin-33; Interleukin-9; Lymphocytes; Proteomics
PubMed: 38597952
DOI: 10.1084/jem.20231236 -
Clinical Therapeutics May 2016The communication of cell injury and death is a critical element in host defense. Although immune cells can serve this function by elaborating cytokines and chemokines,... (Review)
Review
PURPOSE
The communication of cell injury and death is a critical element in host defense. Although immune cells can serve this function by elaborating cytokines and chemokines, somatic cells can repurpose nuclear macromolecules to function as damage-associated molecular patterns (DAMPs) or alarmins to exert similar activity. Among these molecules, DNA, high-mobility group box-1, and histone proteins can all act as DAMPs once they are in an extracellular location. This review describes current information on the role of the nuclear DAMPs, their translocation to the outside of cells, and pathways of activation after uptake into the inside of immune cells.
METHODS
MEDLINE and PubMed databases were searched for citations (1990-2016) in English related to the following terms: DAMPs, high-mobility group box-1, DNA, histones, cell death, danger, and immune activation. Selected articles with the most relevant studies were included for a more detailed consideration.
FINDINGS
Although nuclear molecules have important structural and genetic regulatory roles inside the cell nucleus, when released into the extracellular space during cell death, these molecules can acquire immune activity and serve as alarmins or DAMPs. Although apoptosis is generally considered the source of extracellular nuclear material, other cell death pathways such as necroptosis, NETosis, and pyroptosis can contribute to the release of nuclear molecules. Importantly, the release of nuclear DAMPs occurs with both soluble and particulate forms of these molecules. The activity of nuclear molecules may depend on posttranslational modifications, redox changes, and the binding of other molecules. Once in an extracellular location, nuclear DAMPs can engage the same pattern recognition receptors as do pathogen-associated molecular patterns. These interactions can activate immune cells and lead to cytokine and chemokine production. Among these receptors, internal receptors for DNA are key to the response to this molecule; the likely function of these internal sensors is the recognition of DNA from intracellular infection by bacteria or viruses. Activation of these receptors requires translocation of extracellular DNA into specialized compartments. In addition to nuclear DNA, mitochondrial DNA can also serve as a DAMP.
IMPLICATIONS
The communication of cell injury and death is a critical element in host defense and involves the repurposing of nuclear molecules as immune triggers. As such, the presence of extracellular nuclear material can serve as novel biomarkers for conditions involving cell injury and death. Targeting of these molecules may also represent an important new approach to therapy.
Topics: Alarmins; Animals; Biomedical Research; Cell Death; DNA; Extracellular Space; HMGB1 Protein; Histones; Humans; Immune System Phenomena; Mice
PubMed: 27021604
DOI: 10.1016/j.clinthera.2016.02.029