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Experimental Biology and Medicine... 2024Rheumatoid fibroblast-like synoviocytes (RFLS) have an important role in the inflammatory pathogenesis of rheumatoid arthritis (RA). Toll-like receptor 3 (TLR3) is...
Rheumatoid fibroblast-like synoviocytes (RFLS) have an important role in the inflammatory pathogenesis of rheumatoid arthritis (RA). Toll-like receptor 3 (TLR3) is upregulated in RFLS; its activation leads to the production of interferon-β (IFN-β), a type I IFN. IFN-stimulated gene 56 (ISG56) is induced by IFN and is involved in innate immune responses; however, its role in RA remains unknown. Therefore, the purpose of this study was to investigate the role of TLR3-induced ISG56 in human RFLS. RFLS were treated with polyinosinic-polycytidylic acid (poly I:C), which served as a TLR3 ligand. ISG56, melanoma differentiation-associated gene 5 (MDA5), and C-X-C motif chemokine ligand 10 (CXCL10) expression were measured using quantitative reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Using immunohistochemistry, we found that ISG56 was expressed in synovial tissues of patients with RA and osteoarthritis. Under poly I:C treatment, ISG56 was upregulated in RFLS. In addition, we found that the type I IFN-neutralizing antibody mixture suppressed ISG56 expression. ISG56 knockdown decreased CXCL10 expression and MDA5 knockdown decreased ISG56 expression. In addition, we found that ISG56 was strongly expressed in the synovial cells of patients with RA. TLR3 signaling induced ISG56 expression in RFLS and type I IFN was involved in ISG56 expression. ISG56 was also found to be associated with CXCL10 expression, suggesting that ISG56 may be involved in TLR3/type I IFN/CXCL10 axis, and play a role in RA synovial inflammation.
Topics: Humans; Toll-Like Receptor 3; Arthritis, Rheumatoid; Poly I-C; Signal Transduction; Synoviocytes; Chemokine CXCL10; Interferon-Induced Helicase, IFIH1; Cells, Cultured; Synovial Membrane; Adaptor Proteins, Vesicular Transport; RNA-Binding Proteins; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins
PubMed: 38881847
DOI: 10.3389/ebm.2024.10122 -
Molecular Immunology Jun 20243-phosphoinositide-dependent protein kinase-1 (PDK-1) is a key kinase regulating the activity of the PI3K/AKT pathway and a major regulator of the AGC protein kinase...
3-phosphoinositide-dependent protein kinase-1 (PDK-1) is a key kinase regulating the activity of the PI3K/AKT pathway and a major regulator of the AGC protein kinase family. It is essential in the physiological activities of cells, embryonic development, individual development and immune response. In this study, we have identified for the first time an analogue of PDK-1 in the most primitive vertebrate, lamprey, and named it PDK-1-like. The protein sequence similarity of lamprey PDK-1-like to human, mouse, chicken, African xenopus and zebrafish PDK-1 were 64.4 %, 64.5 %, 65.0 %, 61.3 % and 63.2 %, respectively. The phylogenetic tree showed that PDK-1-like of lamprey were located at the base of the vertebrate branch, in line with the trend of biological evolution. Meanwhile, homology analysis showed that PDK-1 proteins across species shared a conserved kinase structural domain and a Pleckstrin Homology (PH) domain. Genomic synteny analysis revealed that the large-scale duplication blocks were not found in lamprey genome and neighbor genes of lamprey PDK-1-like presented dramatic differences compared with jawed vertebrates. More importantly, qPCR analysis showed that PDK-1-like was widely expressed in lamprey. Its mRNA expression levels varied in response to different pathogenic stimuli, and its expression was generally up-regulated under Polyinosinic-Polycytidylic acid (Poly(I:C)) stimulation. Pearson's correlation analysis showed that PDK-1-like was involved in co-expressed with MyD88-independent TLR-3 pathway during the immune response of lamprey, instead of MyD88-dependent TLR-3 pathway. In summary, our composite results offer valuable clues to the origin and evolution of PDK-1, and imply that PDK-1 s are among the most ancestral immune regulators in vertebrates.
PubMed: 38875755
DOI: 10.1016/j.molimm.2024.06.001 -
Journal of Bone and Mineral Research :... Jun 2024Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies...
Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor by inducing endogenous IFN-I and IFN-stimulated genes (ISGs), their function in bone homeostasis still needs further exploration. Here, our study demonstrates two distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. Firstly, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized (OVX)-induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/- mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impair the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-β signaling pathway.
PubMed: 38874138
DOI: 10.1093/jbmr/zjae093 -
Fish & Shellfish Immunology Jun 2024Type I interferons (IFN-I) play a pivotal role in vertebrate innate immunity against viruses. This study is an analysis of IFN-I genes in an updated version of the...
Type I interferons (IFN-I) play a pivotal role in vertebrate innate immunity against viruses. This study is an analysis of IFN-I genes in an updated version of the Atlantic salmon genome published in 2021 (version Ssal_v3.1), revealing 47 IFN-I genes in the Atlantic salmon genome. The GH1 locus of chromosome (Chr) 3 harbors 9 IFNa genes, 5 IFNb genes, 6 IFNc genes, 11 IFNe genes and 1 IFNf gene. The GH2 locus on Chr6 contains 1 IFNa gene, 12 IFNc genes and 1 IFNf gene while Chr19 carries a single IFNd gene. Intraperitoneal injection of Atlantic salmon presmolts with poly I:C, a mimic of virus double-stranded RNA, significantly up-regulated IFNc genes from both Chr3 and Chr6 in heart, with lower expression in head kidney. IFNe expression increased in the heart, but not in the head kidney while IFNf was strongly up-regulated in both tissues. Antiviral activity of selected IFNs was assessed by transfection of salmon cells with IFN-expressing plasmids followed by infectious pancreatic necrosis virus infection, and by injection of fish with IFN-plasmids followed by measuring expression of the antiviral Mx1 gene. The results demonstrated that IFNc from both Chr3 and Chr6 provided full protection of cells against virus infection, whereas IFNe and IFNf showed lesser protection. IFNc from Chr3 and Chr6 along with IFNe and IFNf, up-regulated the Mx1 gene in the muscle, while only the IFNcs caused induction of Mx1 in liver. Overall, this study reveals that Atlantic salmon possesses an even more potent innate immune defense against viruses than previously understood.
PubMed: 38871143
DOI: 10.1016/j.fsi.2024.109694 -
Nanoscale Advances Jun 2024The interplay between vascularization and macrophage-induced immune suppression plays a crucial role in melanoma treatment. In this study, we propose a novel combination...
The interplay between vascularization and macrophage-induced immune suppression plays a crucial role in melanoma treatment. In this study, we propose a novel combination approach to combat melanoma by simultaneously inhibiting tumor vascularization and enhancing macrophage-mediated anti-tumor responses. We investigate the potential of combining combretastatin A4 (CA4), a vascular-disrupting agent, with poly(I:C) (PIC), an immunostimulatory adjuvant. This combination approach effectively suppresses melanoma cell proliferation, disrupts vascularization, and promotes macrophage polarization towards the M1 phenotype for melanoma suppression. To facilitate efficient co-delivery of CA4 and PIC for enhanced anti-angiogenic immunotherapy, we develop an injectable metal-organic framework hydrogel using Zeolitic Imidazolate Framework-8 (ZIF-8) and hyaluronic acid (HA) (ZIF-8/HA). Our findings demonstrate that ZIF-8 enables efficient loading of CA4 and enhances the stability of PIC against RNAase degradation . Furthermore, the developed co-delivery hydrogel system, PIC/CA4@ZIF-8/HA, exhibits improved rheological properties, good injectability and prolonged drug retention. Importantly, experiments demonstrate that the PIC/CA4@ZIF-8/HA formulation significantly reduces the dosage and administration frequency while achieving a more pronounced therapeutic effect. It effectively inhibits melanoma growth by suppressing angiogenesis, destroying blood vessels, promoting M1 macrophage infiltration, and demonstrating excellent biocompatibility. In conclusion, our study advances anti-angiogenic immunotherapy for melanoma through the potent combination of PIC/CA4, particularly when administered using the PIC/CA4@ZIF-8/HA formulation. These findings provide a new perspective on clinical anti-angiogenic immunotherapy for melanoma, emphasizing the importance of targeting tumor vascularization and macrophage-mediated immune suppression simultaneously.
PubMed: 38868828
DOI: 10.1039/d4na00079j -
Biological & Pharmaceutical Bulletin 2024Long non-coding RNAs (lncRNAs) are sequences longer than 200 nucleotides, but they do not encode proteins. Nevertheless, they have significant roles in diverse...
Long non-coding RNAs (lncRNAs) are sequences longer than 200 nucleotides, but they do not encode proteins. Nevertheless, they have significant roles in diverse biological functions. It remains unclear how viral infections trigger the expression of lncRNAs. In our previous research, we revealed a distinct type of lncRNAs with a lifespan under 4 h in human HeLa cells. These short-lived lncRNAs might be associated with numerous regulatory roles. Given their potential impact on human physiology, these short-lived lncRNAs could be key indicators to measure polyinosinic:polycytidylic acid (poly I:C) stimulation. In our recent work, we discovered three lncRNAs: IDI2-AS1, OIP5-AS1, and LITATS1. After exposure to poly I:C, imitating viral assault in human A549 cells, IDI2-AS1 levels dropped significantly while OIP5-AS1 and LITATS1 levels rose markedly. Our results indicate that short-lived lncRNAs respond to poly I:C stimulation, exhibiting substantial changes in expression. This indicates that the understanding the role of lncRNAs in the host response to viral infection and the potential for these molecules to serve as novel therapeutic targets.
Topics: RNA, Long Noncoding; Humans; Poly I-C; A549 Cells; HeLa Cells
PubMed: 38866523
DOI: 10.1248/bpb.b24-00037 -
Immunity, Inflammation and Disease Jun 2024Astragaloside IV (AS-IV) is the most active monomer in the traditional Chinese herbal medicine Radix Astragali, which has a wide range of antiviral, anti-inflammatory,...
Astragaloside IV inhibits inflammation caused by influenza virus via reactive oxygen species/NOD-like receptor thermal protein domain associated protein 3/Caspase-1 signaling pathway.
BACKGROUND
Astragaloside IV (AS-IV) is the most active monomer in the traditional Chinese herbal medicine Radix Astragali, which has a wide range of antiviral, anti-inflammatory, and antifibrosis pharmacological effects, and shows protective effects in acute lung injury.
METHODS
This study utilized the immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, and hematoxylin and eosin staining methods to investigate the mechanism of AS-IV in reducing viral pneumonia caused by influenza A virus in A549 cells and BALB/c mice.
RESULTS
The results showed that AS-IV suppressed reactive oxygen species production in influenza virus-infected A549 cells in a dose-dependent manner, and subsequently inhibited the activation of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 inflammasome and Caspase-1, decreased interleukin (IL) -1β and IL-18 secretion. In BALB/c mice infected with Poly (I:C), oral administration of AS-IV can significantly reduce Poly (I:C)-induced acute pneumonia and lung pathological injury.
CONCLUSIONS
AS-IV alleviates the inflammatory response induced by influenza virus in vitro and lung flammation and structural damage caused by poly (I:C) in vivo.
Topics: Animals; Saponins; Triterpenes; Mice; Signal Transduction; Humans; Reactive Oxygen Species; Mice, Inbred BALB C; A549 Cells; Caspase 1; Orthomyxoviridae Infections; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammation; Influenza A virus; Anti-Inflammatory Agents
PubMed: 38860765
DOI: 10.1002/iid3.1309 -
Veterinary Microbiology Jun 2024Water buffalo Hunnivirus (BufHuV) belongs to the family Picornaviridae and is a newly discovered member of the Hunnivirus A genus. It causes intestinal diseases in...
Water buffalo Hunnivirus (BufHuV) belongs to the family Picornaviridae and is a newly discovered member of the Hunnivirus A genus. It causes intestinal diseases in cattle, mainly lead to subclinical infections, thereby seriously threatening the health of cattle herds. In addition, it can also bring about various clinical disease syndromes which results in severe economic losses to the cattle industry. To date, there have been no reports worldwide on the study of Hunnivirus virus infecting host cells and causing innate immune responses. In this study, we found that interferon treatment effectively blocked BufHuV replication and infection with the virus weakened the host antiviral responses. Inhibiting the transcription of IFN-β and ISGs induced by either Sendai virus (SeV) or poly(I:C) in MDBK and HCT-8 cells, were dependent on the IRF3 or NF-κB signaling pathways, and this inhibited the activation of IFN-β promoter by TBK1 and its upstream molecules, RIGI and MDA5. By constructing and screening five BufHuV proteins, we found that VP2, 2 C, 3 C and 3D inhibited the activation of IFN-β promoter induced by SeV. Subsequently, we showed that VP2 inhibited the activation of IRF3 induced by SeV or poly (I:C), and it inhibited IRF3 activation by inhibiting its phosphorylation and nuclear translocation. In addition, we confirmed that VP2 inhibited the activation of IFNβ induced by signaling molecules, MDA5 and TBKI. In summary, these findings provide new insights into the pathogenesis of Hunnivirus and its mechanisms involved in evading host immune responses.
PubMed: 38851152
DOI: 10.1016/j.vetmic.2024.110148 -
Phytomedicine : International Journal... Aug 2024Psoriasis, a chronic immune-mediated skin disease with pathological features such as aberrant differentiation of keratinocytes, dermal-epidermal inflammation, and...
BACKGROUND
Psoriasis, a chronic immune-mediated skin disease with pathological features such as aberrant differentiation of keratinocytes, dermal-epidermal inflammation, and angiogenesis. 2,3,5,4'-Tetrahydroxy stilbene 2-Ο-β-d-glucoside (2354Glu) is a natural small molecule polyhydrostilbenes isolated from Polygonum multiglorum Thunb. The regulation of IL-36 subfamily has led to new pharmacologic strategies to reverse psoriasiform dermatitis.
PURPOSE
Here we investigated the therapeutic potential of 2354Glu and elucidated the underlying mechanism in psoriasis.
METHODS
The effects of 2354Glu on IL-36 signaling were assessed by psoriasiform in vivo, in vitro and ex vivo model. The in vivo mice model of psoriasis-like skin inflammation was established by applying imiquimod (IMQ), and the in vitro and ex vitro models were established by stimulating mouse primary keratinocyte, human keratinocytes cells (HaCaT) and ex vivo skin tissue isolated from the mice back with Polyinosine-polycytidylic acid (Poly(I:C)), IMQ, IL-36γ and Lipopolysaccharide (LPS) respectively. Moreover, NETs formation was inhibited by Cl-amidine to evaluate the effect of NETs in psoriatic mouse model. The effects of 2354Glu on skin inflammation were assessed by western blot, H&E, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay and real-time quantitative PCR.
RESULTS
In Poly(I:C)-stimulated keratinocytes, the secretion of IL-36 was inhibited after treatment with 2354Glu, similar to the effects of TLR3, P2X7R and caspase-1 inhibitors. In aldara (imiquimod)-induced mice, 2354Glu (100 and 25 mg/kg) improved immune cell infiltration and hyperkeratosis in psoriasis by directly targeting IL-36 in keratinocytes through P2X7R-caspase-1. When treatment with 2354Glu (25 mg/kg) was insufficient to inhibit IL-36γ, NETs reduced pathological features and IL-36 signaling by interacting with keratinocytes to combat psoriasis like inflammation.
CONCLUSION
These results indicated that NETs had a beneficial effect on psoriasiform dermatitis. 2354Glu alleviates psoriasis by directly targeting IL-36/P2X7R axis and NET formation, providing a potential candidate for the treatment of psoriasis.
Topics: Animals; Psoriasis; Glucosides; Humans; Interleukin-1; Stilbenes; Mice; Imiquimod; Disease Models, Animal; Keratinocytes; Polygonum; Skin; Mice, Inbred BALB C; Signal Transduction; Male; Caspase 1
PubMed: 38838402
DOI: 10.1016/j.phymed.2024.155783 -
The Journal of Dermatology Jun 2024
Proposal of a cutaneous lupus erythematosus-like keratinocyte model in vitro under local conditions using interferon-alpha and Poly I:C and its use in examining the therapeutic effects of tyrosine kinase 2 inhibitor.
PubMed: 38831616
DOI: 10.1111/1346-8138.17318