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Annals of the Rheumatic Diseases Apr 2023Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal...
OBJECTIVES
Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA.
METHODS
RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape.
RESULTS
Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14CD86GLUT1MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80iNOSRAPTORMΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1 animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation.
CONCLUSION
The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).
Topics: Animals; Humans; Arthritis, Rheumatoid; Endothelial Cells; Macrophages; Monokines; Syndecan-1; Synovial Fluid; Synovial Membrane; Syntenins; Th1 Cells; TOR Serine-Threonine Kinases
PubMed: 36593091
DOI: 10.1136/ard-2022-223284 -
Inflammatory Bowel Diseases Feb 2023Patient-derived organoid (PDO) models offer potential to transform drug discovery for inflammatory bowel disease (IBD) but are limited by inconsistencies with...
BACKGROUND
Patient-derived organoid (PDO) models offer potential to transform drug discovery for inflammatory bowel disease (IBD) but are limited by inconsistencies with differentiation and functional characterization. We profiled molecular and cellular features across a range of intestinal organoid models and examined differentiation and establishment of a functional epithelial barrier.
METHODS
Patient-derived organoids or monolayers were generated from control or IBD patient-derived colon or ileum and were molecularly or functionally profiled. Biological or technical replicates were examined for transcriptional responses under conditions of expansion or differentiation. Cell-type composition was determined by deconvolution of cell-associated gene signatures and histological features. Differentiated control or IBD-derived monolayers were examined for establishment of transepithelial electrical resistance (TEER), loss of barrier integrity in response to a cocktail of interferon (IFN)-γ and tumor necrosis factor (TNF)-α, and prevention of cytokine-induced barrier disruption by the JAK inhibitor, tofacitinib.
RESULTS
In response to differentiation media, intestinal organoids and monolayers displayed gene expression patterns consistent with maturation of epithelial cell types found in the human gut. Upon differentiation, both colon- and ileum-derived monolayers formed functional barriers, with sustained TEER. Barrier integrity was compromised by inflammatory cytokines IFN-γ and TNF-α, and damage was inhibited in a dose-dependent manner by tofacitinib.
CONCLUSIONS
We describe the generation and characterization of human colonic or ileal organoid models capable of functional differentiation to mature epithelial cell types. In monolayer culture, these cells formed a robust epithelial barrier with sustained TEER and responses to pharmacological modulation. Our findings demonstrate that control and IBD patient-derived organoids possess consistent transcriptional and functional profiles that can enable development of epithelial-targeted therapies.
Topics: Humans; Cytokines; Epithelial Cells; Inflammatory Bowel Diseases; Intestinal Mucosa; Organoids; Tumor Necrosis Factor-alpha; Intestines
PubMed: 36356046
DOI: 10.1093/ibd/izac212 -
Nature Immunology May 2023Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated...
Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible.
Topics: Animals; Mice; Bone Marrow Transplantation; Cytokines; Granulocyte Colony-Stimulating Factor; Interleukin-1; Tumor Necrosis Factor-alpha; Immunologic Deficiency Syndromes
PubMed: 36997670
DOI: 10.1038/s41590-023-01473-6 -
Hepatology (Baltimore, Md.) Aug 2020The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these...
BACKGROUND AND AIMS
The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these diseases is unclear, as no IL-1β receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines.
APPROACH AND RESULTS
AML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1β, which was markedly amplified by TNF co-treatment. IL-1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1β/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1β/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1β/TNF in combination, but neither IL-1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1β/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns.
CONCLUSIONS
The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1β/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.
Topics: Animals; Autophagy; Cells, Cultured; Female; Hepatocytes; Inflammation; Interleukin-1beta; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha
PubMed: 32108953
DOI: 10.1002/hep.31209 -
Autoimmunity Reviews Mar 2021The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell... (Review)
Review
The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet's syndrome, Sjogren Syndrome, and cancer. This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL-1 soluble receptor rilonacept, and the IL-1 receptor antagonist anakinra. These advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine in a broad spectrum of diseases.
Topics: COVID-19; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Receptors, Interleukin-1; SARS-CoV-2
PubMed: 33482337
DOI: 10.1016/j.autrev.2021.102763 -
International Journal of Molecular... Nov 2022Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric... (Review)
Review
Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.
Topics: Humans; Neoplasms; Interleukin-1
PubMed: 36499246
DOI: 10.3390/ijms232314918 -
Cardiovascular Diabetology Jan 2024Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic...
BACKGROUND
Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized.
OBJECTIVE
The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation.
METHODS
Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study.
RESULTS
The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01-1.04, p = 1.17e-04 and 1.03, 95% CI 1.01-1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01-1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001-1.01, p = 4.9e-2).
CONCLUSION
The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM.
Topics: Humans; Diabetes Mellitus, Type 1; Genome-Wide Association Study; Interferon-gamma; Mendelian Randomization Analysis; Myocardial Ischemia; Monokines; Cardiomyopathies; Polymorphism, Single Nucleotide
PubMed: 38218861
DOI: 10.1186/s12933-023-02117-7 -
Acta Neurologica Scandinavica Oct 2022Robust and accessible biomarkers are greatly needed in epilepsy. Diagnostic and prognostic precision in the clinic needs to improve, and there is a need for objective... (Review)
Review
Robust and accessible biomarkers are greatly needed in epilepsy. Diagnostic and prognostic precision in the clinic needs to improve, and there is a need for objective quantification of seizure burden. In recent years, there have been advances in the development of accessible and cost-effective blood-based biomarkers in neurology, and these are increasingly studied in epilepsy. However, the field is in its infancy and specificity and sensitivity for most biomarkers in most clinical situations are not known. This review describes advancements regarding human blood biomarkers in epilepsy. Examples of biochemical markers that have been shown to have higher blood concentrations in study subjects with epilepsy include brain proteins like S100B or neuronal specific enolase, and neuroinflammatory proteins like interleukins, and tumor necrosis factor-alpha. Some of the blood biomarkers also seem to reflect seizure duration or frequency, and levels decrease in response to treatment with antiseizure medication. For most biomarkers, the literature contains seemingly conflicting results. This is to be expected in an emerging field and could reflect different study populations, sampling or analysis techniques, and epilepsy classification. More studies are needed with emphasis put on the classification of epilepsy and seizure types. More standardized reporting could perhaps decrease result heterogeneity and increase the potential for data sharing and subgroup analyses.
Topics: Biomarkers; Epilepsy; Humans; Phosphopyruvate Hydratase; Seizures; Tumor Necrosis Factor-alpha
PubMed: 35411571
DOI: 10.1111/ane.13616 -
MMW Fortschritte Der Medizin Nov 2021
Topics: Humans; Rheumatic Diseases; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 34767199
DOI: 10.1007/s15006-021-0519-y -
Blood Feb 2023
Topics: Humans; Clonal Hematopoiesis; Aging; Inflammation; Signal Transduction; Interleukin-1; DNA-Binding Proteins; Dioxygenases
PubMed: 36821185
DOI: 10.1182/blood.2022019104