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Nature Reviews. Rheumatology Sep 2023The cytokine TNF signals via two distinct receptors, TNF receptor 1 (TNFR1) and TNFR2, and is a central mediator of various immune-mediated diseases. Indeed,... (Review)
Review
The cytokine TNF signals via two distinct receptors, TNF receptor 1 (TNFR1) and TNFR2, and is a central mediator of various immune-mediated diseases. Indeed, TNF-neutralizing biologic drugs have been in clinical use for the treatment of many inflammatory pathological conditions, including various rheumatic diseases, for decades. TNF has pleiotropic effects and can both promote and inhibit pro-inflammatory processes. The integrated net effect of TNF in vivo is a result of cytotoxic TNFR1 signalling and the stimulation of pro-inflammatory processes mediated by TNFR1 and TNFR2 and also TNFR2-mediated anti-inflammatory and tissue-protective activities. Inhibition of the beneficial activities of TNFR2 might explain why TNF-neutralizing drugs, although highly effective in some diseases, have limited benefit in the treatment of other TNF-associated pathological conditions (such as graft-versus-host disease) or even worsen the pathological condition (such as multiple sclerosis). Receptor-specific biologic drugs have the potential to tip the balance from TNFR1-mediated activities to TNFR2-mediated activities and enable the treatment of diseases that do not respond to current TNF inhibitors. Accordingly, a variety of reagents have been developed that either selectively inhibit TNFR1 or selectively activate TNFR2. Several of these reagents have shown promise in preclinical studies and are now in, or approaching, clinical trials.
Topics: Humans; Receptors, Tumor Necrosis Factor, Type II; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha; Cytokines; Rheumatic Diseases
PubMed: 37542139
DOI: 10.1038/s41584-023-01002-7 -
Trends in Immunology Aug 2023Tumor necrosis factor (TNF) plays a central role in orchestrating mammalian inflammatory responses. It promotes inflammation either directly by inducing inflammatory... (Review)
Review
Tumor necrosis factor (TNF) plays a central role in orchestrating mammalian inflammatory responses. It promotes inflammation either directly by inducing inflammatory gene expression or indirectly by triggering cell death. TNF-mediated cell death-driven inflammation can be beneficial during infection by providing cell-extrinsic signals that help to mount proper immune responses. Uncontrolled cell death caused by TNF is instead highly detrimental and is believed to cause several human autoimmune diseases. Death is not the default response to TNF sensing. Molecular brakes, or cell death checkpoints, actively repress TNF cytotoxicity to protect the organism from its detrimental consequences. These checkpoints therefore constitute essential safeguards against inflammatory diseases. Recent advances in the field have revealed the existence of several new and unexpected brakes against TNF cytotoxicity and pathogenicity.
Topics: Animals; Humans; Necrosis; Apoptosis; Signal Transduction; Receptor-Interacting Protein Serine-Threonine Kinases; Cell Death; Tumor Necrosis Factor-alpha; Inflammation; Mammals
PubMed: 37357102
DOI: 10.1016/j.it.2023.05.007 -
Cancer Cell Jan 2024Cells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of...
Cells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) is integral to anti-tumor immune responses, our understanding of the spatiotemporal behavior of these cytokines is limited. Here, we describe a single cell transcriptome-based approach to infer which signal(s) an individual cell has received. We demonstrate that, contrary to expectations, CD8 T cell-derived IFNγ is the dominant modifier of the TME relative to TNFα. Furthermore, we demonstrate that cell pools that show abundant IFNγ sensing are characterized by decreased expression of transforming growth factor β (TGFβ)-induced genes, consistent with IFNγ-mediated TME remodeling. Collectively, these data provide evidence that CD8 T cell-secreted cytokines should be categorized into local and global tissue modifiers, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the TME.
Topics: Humans; Cytokines; Tumor Necrosis Factor-alpha; Tumor Microenvironment; Interferon-gamma; CD8-Positive T-Lymphocytes
PubMed: 38194914
DOI: 10.1016/j.ccell.2023.12.010 -
Nature Nanotechnology Mar 2024Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived...
Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1β secretion. The elevated interleukin-1β increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.
Topics: Animals; Mice; Interleukin-1beta; Trained Immunity; Vaccination; Neoplasms; Lymphocyte Activation; Antigens, Neoplasm; Bacteria
PubMed: 38052943
DOI: 10.1038/s41565-023-01553-6 -
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 -
Frontiers in Immunology 2023In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat... (Review)
Review
In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques.
Topics: Humans; Psoriasis; Keratinocytes; Skin; Interleukins; Tumor Necrosis Factor-alpha
PubMed: 38022549
DOI: 10.3389/fimmu.2023.1286344 -
Pharmacology & Therapeutics Nov 2023More than a decade ago IL-1 blockade was suggested as an add-on therapy for the treatment of cancer. This proposal was based on the overall safety record of anti-IL-1... (Review)
Review
More than a decade ago IL-1 blockade was suggested as an add-on therapy for the treatment of cancer. This proposal was based on the overall safety record of anti-IL-1 biologics and the anti-tumor properties of IL-1 blockade in animal models of cancer. Today, a new frontier in IL-1 activity regulation has developed with several orally active NLRP3 inhibitors currently in clinical trials, including cancer. Despite an increasing body of evidence suggesting a role of NLRP3 and IL-1-mediated inflammation driving cancer initiation, immunosuppression, growth, and metastasis, NLRP3 activation in cancer remains controversial. In this review, we discuss the recent advances in the understanding of NLRP3 activation in cancer. Further, we discuss the current opportunities for NLRP3 inhibition in cancer intervention with novel small molecules.
Topics: Animals; Inflammasomes; Inflammation; Interleukin-1; Neoplasms; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species
PubMed: 37866732
DOI: 10.1016/j.pharmthera.2023.108545 -
International Orthopaedics Aug 2023Apoptosis is an important physiological process, making a great difference to development and tissue homeostasis. Osteoarthritis (OA) is a chronic joint disease... (Review)
Review
PURPOSE
Apoptosis is an important physiological process, making a great difference to development and tissue homeostasis. Osteoarthritis (OA) is a chronic joint disease characterized by degeneration and destruction of articular cartilage and bone hyperplasia. This purpose of this study is to provide an updated review of the role of apoptosis in the pathogenesis of osteoarthritis.
METHODS
A comprehensive review of the literature on osteoarthritis and apoptosis was performed, which mainly focused on the regulatory factors and signaling pathways associated with chondrocyte apoptosis in osteoarthritis and other pathogenic mechanisms involved in chondrocyte apoptosis.
RESULTS
Inflammatory mediators such as reactive oxygen species (ROS), nitric oxide (NO), IL-1β, tumor necrosis factor-α (TNF-α), and Fas are closely related to chondrocyte apoptosis. NF-κB signaling pathway, Wnt signaling pathway, and Notch signaling pathway activate proteins and gene targets that promote or inhibit the progression of osteoarthritis disease, including chondrocyte apoptosis and ECM degradation. Long non-coding RNAs (LncRNAs) and microRNAs (microRNAs) have gradually replaced single and localized research methods and become the main research approaches. In addition, the relationship between cellular senescence, autophagy, and apoptosis was also briefly explained.
CONCLUSION
This review offers a better molecular delineation of apoptotic processes that may help in designing new therapeutic options for OA treatment.
Topics: Humans; Osteoarthritis; Chondrocytes; MicroRNAs; Signal Transduction; Apoptosis; Interleukin-1beta
PubMed: 37294429
DOI: 10.1007/s00264-023-05847-1 -
Current Cardiology Reports Sep 2023We review the pathophysiology, diagnosis, and contemporary treatment for recurrent pericarditis, with focus on interleukin-1 (IL-1) inhibitors. (Review)
Review
PURPOSE OF THE REVIEW
We review the pathophysiology, diagnosis, and contemporary treatment for recurrent pericarditis, with focus on interleukin-1 (IL-1) inhibitors.
RECENT FINDINGS
Recurrent pericarditis occurs in about 15-30% of patients who have acute pericarditis. With increased understanding of the autoinflammatory pathophysiology of recurrent pericarditis, IL-1 inhibitors including anakinra, canakinumab, and rilonacept have been applied to this condition with great promise. In particular, the RHAPSODY trial found rilonacept significantly improves pain and inflammation, while also reducing recurrence with few adverse events. The next IL-1 inhibitor on the block for pericarditis, goflikicept, is also discussed. Understanding the role of the inflammasome via the autoinflammatory pathway in pericarditis has led to incorporation of IL-1 inhibitors in the treatment of recurrent pericarditis, with proven efficacy and safety and randomized trials. This will lead to increase uptake of this agent which demonstrated lower rates of recurrence and faster time to resolution.
Topics: Humans; Pericarditis; Inflammation; Interleukin 1 Receptor Antagonist Protein; Recurrence; Interleukin-1
PubMed: 37458866
DOI: 10.1007/s11886-023-01912-8 -
Journal of Medicinal Chemistry Nov 2023NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of... (Review)
Review
NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1β and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Diabetes Mellitus, Type 2; Interleukin-1beta; Arthritis, Rheumatoid; Pyroptosis
PubMed: 37879043
DOI: 10.1021/acs.jmedchem.3c01370