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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 -
Current Topics in Behavioral... 2021Neuroinflammation is the central nervous system's response to: injury, infection, and abnormal neural activity. Inflammatory processes are known to mediate many... (Review)
Review
Neuroinflammation is the central nervous system's response to: injury, infection, and abnormal neural activity. Inflammatory processes are known to mediate many diseases, and recently evidence indicates that neuroinflammation underlies hearing disorders such as presbyacusis, middle-ear disease, ototoxicity, noise-induced hearing loss, and tinnitus. This chapter provides a review of the role of neuroinflammation in the etiology and treatment of tinnitus. Specifically, our research team has demonstrated that both tumor necrosis factor alpha (TNF-α) and calpain signaling pathways are involved in noise-induced tinnitus and that blocking them yielded therapeutic effects on tinnitus. Other efforts such as controlling acute inflammatory response via specialized pro-resolving mediators may help provide insight into preventing and treating tinnitus-related inflammatory processes.
Topics: Humans; Inflammation; Signal Transduction; Tinnitus; Tumor Necrosis Factor-alpha
PubMed: 34282564
DOI: 10.1007/7854_2021_238 -
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 -
Inflammatory Bowel Diseases May 2023Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis...
BACKGROUND
Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis factor (anti-TNF)-α inadequate responders (TNF-IRs). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab.
METHODS
Eight tissue transcriptomic data sets from IBD patients treated with anti-TNF-α therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. The RNAseq colon tissue data from clinical studies of TNF-IR Crohn's disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab.
RESULTS
We found 7 TNF-IR upregulated modules related to innate/adaptive immune responses, interferon signaling, and tissue remodeling and 6 TNF-IR upregulated cell types related to inflammatory fibroblasts, postcapillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR upregulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, 4 of the 6 TNF-IR upregulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab.
CONCLUSIONS
Collectively, these data suggest that upadacitinib and risankizumab affect TNF-IR upregulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.
Topics: Humans; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Inflammatory Bowel Diseases
PubMed: 36515243
DOI: 10.1093/ibd/izac246 -
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 -
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 -
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 -
Cytokine Sep 2022Cellular communication mediated by cytokines is an important mechanism dictating immune responses, their cross talk and final immune output. Cytokines play a major role... (Review)
Review
Cellular communication mediated by cytokines is an important mechanism dictating immune responses, their cross talk and final immune output. Cytokines play a major role in dictating the immune outcome to cancer by regulating the events of development, differentiation and activation of innate immune cells. Cytokines are pleiotropic in nature, hence understanding their role individually or as member of network cytokines is critical to delineate their role in tumour immunity. Tumour systemically manipulates the immune system to evade and escape immune recognition for their uncontrollable growth and metastasis. The developing tumour comprise a large and diverse set of myeloid cells which are vulnerable to manipulation by the tumour-microenvironment. The innate immune cells of the monocytic lineage skew the fate of the adaptive immune cells and thus dictating cancer elimination or progression. Targeting cells at tumour cite is preposterous owing to their tight network, poor reach and abundance of immunosuppressive mechanisms. Monocytic lineage-derived cytokines (monokines) play crucial role in tumour regression or progression by either directly killing the tumour cells with TNFα or promoting its growth by TGFβ. In addition, the monokines like IL-12, IL-1β, IL-6, IL-10 and TGFβ direct the adaptive immune cells to secrete anti-tumour cytokines, TNFα, IFNγ, perforin and granzyme or pro-tumour cytokines, IL-10 and TGFβ. In this review, we elucidate the roles of monokines in dictating the fate of tumour by regulating responses at various stages of generation, differentiation and activation of immune cells along with the extensive cross talk. We have attempted to delineate the synergy and antagonism of major monokines among themselves or with tumour-derived or adaptive immune cytokines. The review provides an update on the possibilities of placing monokines to potential practical use as cytokine therapy against cancer.
Topics: Cytokines; Humans; Interleukin-10; Monocytes; Monokines; Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment; Tumor Necrosis Factor-alpha
PubMed: 35764025
DOI: 10.1016/j.cyto.2022.155948 -
International Journal of Molecular... Dec 2022The IL-1 superfamily of cytokines is a central regulator of immunity and inflammation. The family is composed of 11 cytokines (with agonist, antagonist, and... (Review)
Review
The IL-1 superfamily of cytokines is a central regulator of immunity and inflammation. The family is composed of 11 cytokines (with agonist, antagonist, and anti-inflammatory properties) and 10 receptors, all tightly regulated through decoy receptor, receptor antagonists, and signaling inhibitors. Inflammation not only is an important physiological response against infection and injury but also plays a central role in atherosclerosis development. Several clinical association studies along with experimental studies have implicated the IL-1 superfamily of cytokines and its receptors in the pathogenesis of cardiovascular disease. Here, we summarize the key features of the IL-1 family, its role in immunity and disease, and how it helps shape the development of atherosclerosis.
Topics: Humans; Interleukin-1; Cytokines; Atherosclerosis; Inflammation; Cardiovascular Diseases
PubMed: 36613465
DOI: 10.3390/ijms24010017