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摘要： Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known on its complex activation processes and role in the progression of beta cell failure. We presently show that two T1D candidate genes (i.e. and ) modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the short-term phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the long-term phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of the chemokine , but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast (detectable after 4h) but transitory (back to basal by 24h) while STAT1-S727 increases slowly (peak at 48h) and is associated with the long-term effects of IFN-α exposure. These pathways can be chemically dissociated in human beta cells by the use of JAK1/2, TYK2 or JNK1 inhibitors. The present findings provide a novel understanding of the dynamics of STAT1 activation and will be useful to develop novel and hopefully targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases.

关键词： WIF1   Wnt5a/MAPK-JNK signaling   DNA methylation   Ankylosing spondylitis   Inflammatory injury  

摘要： The activity of Wnt inhibitory factor 1 (WIF1) is reduced upon promoter methylation and is involved in cartilage degradation in osteoarthritis. This study aims to investigate the mechanism by which WIF1 methylation is involved in chondrocyte damage in ankylosing spondylitis (AS). A model of chondrocyte inflammatory injury in AS was constructed by stimulation with interleukin (IL)-17. WIF1 level in injured chondrocytes was detected by western blot and RT-qPCR. ELISA kits were used to assess the levels of inflammatory cytokines. The expressions of MMP9, MMP13, collagen II, and ADAMTS-4 were tested by western blot and RT-qPCR. Wnt5a/mMAPK signaling and associated phosphorylated protein expressions were observed using western blot. After overexpression of Wnt5a, the same assays were used to evaluate the above indexes. The methylation level of the WIF1 promoter was measured by MSP-PCR assay. WIF1 expression declined in IL-17-induced chondrocytes. Overexpression of WIF1 decreased the levels of inflammatory factors TNF alpha, IL-1 beta, and IL-6, as well as downregulated the expressions of MMP9, MMP13, collagen II, and ADAMTS-4. Likewise, elevated WIF1 inhibited the Wnt5a/MAPK signaling and phosphorylation of JNK. However, upregulation of Wnt5a in IL-17-treated chondrocytes attenuated these responses. Besides, in damaged chondrocytes, WIF1 expression was reduced due to promoter methylation, while it was upregulated after demethylation. In summary, WIF1 exhibits high methylation levels in AS and is involved in inflammatory injury and matrix degradation in chondrocytes by regulating the Wnt5a/MAPK-JNK pathway.

关键词： Interleukin (IL)-17   T helper-17   Systemic autoinflammatory diseases (SAIDs)   IL-17 inhibitors  

摘要： Interleukin (IL)-17, a pro-inflammatory cytokine, plays a pivotal role in immune regulation by bridging innate and adaptive responses. Beyond its canonical involvement in T helper-17 cells-mediated immunity, IL-17 contributes significantly to the pathogenesis of systemic autoinflammatory diseases (SAIDs) including Familial Mediterranean Fever (FMF), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-associated autoinflammatory diseases, and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Dysregulated IL-17 signaling drives inflammasome activation, neutrophil recruitment, and chronic tissue inflammation. IL-17 inhibitors have demonstrated efficacy in refractory SAIDs, though challenges such as increased infection risks, paradoxical inflammatory reactions, and uncertainties regarding long-term safety persist. Currently, there is insufficient data to support the use of IL-17 inhibitors as first-line treatments, and their role in managing SAIDs is yet to be fully defined. This review highlights the mechanistic role of IL-17 in SAIDs and emerging therapeutic strategies, including IL-17-targeted monotherapies and combination approaches with IL-1 or tumor necrosis factor (TNF) inhibitors. Future research should focus on biomarker development, combination therapies, and long-term studies to optimize the safety and efficacy of IL-17-targeted therapies in SAIDs.

摘要： Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

关键词： IL-23   IL-23p19 subunit inhibitors   guselkumab   risankizumab   CD64   in vitro cellular assays   RNA sequencing   immune-mediated inflammatory diseases  

摘要： IL-23 is implicated in the pathogenesis of immune-mediated inflammatory diseases, and myeloid cells that express Fc gamma receptor 1 (Fc gamma RI or CD64) on their surface have been recently identified as a primary source of IL-23 in inflamed tissue. Our complementary analyses of transcriptomic datasets from psoriasis and IBD showed increased expression of CD64 and IL-23 transcripts in inflamed tissue, and greater abundance of cell types with co-expression of CD64 and IL-23. These findings led us to explore potential implications of CD64 binding on the function of IL-23-targeting monoclonal antibodies (mAbs). Guselkumab and risankizumab are mAbs that target the IL-23p19 subunit. Guselkumab has a native Fc domain while risankizumab contains mutations that diminish binding to Fc gamma Rs. In flow cytometry assays, guselkumab, but not risankizumab, showed Fc-mediated binding to CD64 on IFN gamma-primed monocytes. Guselkumab bound CD64 on IL-23-producing inflammatory monocytes and simultaneously captured IL-23 secreted from these cells. Guselkumab binding to CD64 did not induce cytokine production. In live-cell confocal imaging of CD64+ macrophages, guselkumab, but not risankizumab, mediated IL-23 internalization to low-pH intracellular compartments. Guselkumab and risankizumab demonstrated similar potency for inhibition of IL-23 signaling in cellular assays with exogenous addition of IL-23. However, in a co-culture of IL-23-producing CD64+ THP-1 cells with an IL-23-responsive reporter cell line, guselkumab demonstrated Fc-dependent enhanced potency compared to risankizumab for inhibiting IL-23 signaling. These in vitro data highlight the potential for guselkumab binding to CD64 in inflamed tissue to contribute to the potent neutralization of IL-23 at its cellular source.

关键词： HLA   multiple sclerosis   MS   bibliometric analysis   HLA-DRB1   genetic susceptibility  

摘要： Background Multiple sclerosis (MS) is a complex autoimmune disease that affects the central nervous system (CNS) with genetic and environmental factors playing a significant role in its development and progression. One of the most important genetic factors associated with MS is the HLA gene complex. The relationship between HLA and MS has been the subject of numerous studies, but no bibliometric analysis of this research has been reported to date. Therefore, this study aimed to provide a comprehensive overview of the publication output, citation impact, collaboration patterns, and research topics related to HLA and *** A bibliometric analysis of 488 studies published between 1988 and 2023 was conducted using RStudio, Tableau and VOSviewer *** The results indicated an increasing trend in the number of publications and citations over time, with the highest productivity and impact coming from researchers in the United States, Italy and Sweden. The analysis also revealed collaboration networks among researchers and institutions, with the most common research topics being the association of HLA alleles with MS susceptibility, disease course, and treatment response. This study's limitations stem from the inherent biases associated with bibliometric analysis, including database and coverage bias, citation bias, and biases related to accessibility and open access. Additionally, the exclusion of non-English language articles represents a further *** Overall, this bibliometric analysis provides valuable insight into the research landscape of HLA and MS, highlighting the areas that have received the most attention and identifying potential avenues for future research.

关键词： IL-17A   RORγt   inflammation   inverse agonist   liver fibrosis  

摘要： Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by RORγt and produced by Th17 CD4+ and γδ-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel RORγt inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL/6 mice received 2 weekly injections of CCl4 for 4 weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P < 0.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and γδ-T cells, P < 0.05), and myeloid (CD11b+) cells (P = 0.04), most significantly eosinophils (P < 0.05). Furthermore, IL-17A production by CD4+ and γδ-T cells was diminished (P < 0.05 and P < 0. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and ɑ-smooth muscle actin [ɑ-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgfβ) (P < 0.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.

关键词： Atrial fibrillation   atrial fibroblasts   Ang II   IL-11   oxidative stress   mitochondrial dysfunction   autophagy  

摘要： This study aimed to investigate potential targets for the pathogenesis of atrial fibrillation to facilitate the development of effective treatments. Atrial fibroblasts were isolated and stimulated with 1 mu M angiotensin-II (Ang-II) for 24 h. To increase interleukin 11 (IL-11) expression, overexpression plasmids were transfected into atrial fibroblasts. The role and the underlying mechanism of IL-11 in atrial fibrillation were examined by immunofluorescence, measurements of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP), and western blotting assays. Results demonstrated that IL-11 was upregulated in Ang-II-elicited atrial fibroblasts. Ang-II treatment increases alpha-smooth muscle actin (alpha-SMA), ROS and MMP levels, and p62 expression but decreases microtubule-associated protein light chain 3 II/I (LC3 II/I) and Beclin-1 expressions in atrial fibroblasts. These effects were further amplified by IL-11 overexpression. Mechanistically, the mammalian target of rapamycin (mTOR) pathway expression was enhanced in Ang-II-induced atrial fibroblasts, which was further elevated by IL-11 upregulation. IL-11 facilitates Ang II-induced differentiation of atrial fibroblasts into myofibroblasts by promoting oxidative stress, mitochondrial dysfunction, and autophagy inhibition through the mTOR pathway.

关键词： Interleukin 8   Metastasis   EMT   Migration   Invasion   Angiogenesis   Therapy optimization   Immunotherapy improvement  

摘要： Tumors are structures of high complexity. Plurality of their structural and functional components- heterogeneity, diversity, directionality, interdependence and integration of signaling pathways- seem to follow isolated local rules, whereby a superordinate structure remains largely unknown. Understanding the complexity of cancer is the mainstay in finding determinants and developing effective therapies. Interleukin 8 (IL-8) is a potent proinflammatory chemokine that is significantly elevated in many different tumor entities. In contrast to its initially postulated anti-tumor properties, an increasing number of studies have been published in recent years linking this chemokine with tumor-promoting features and poor prognosis. This review summarizes the current state and diversity of the role of IL-8 in the development of cancer.

关键词： Hymenolepis nana   Immune responses   Excretory-secretory products   RCM-1   Tuft/IL-13   FOXM1  

摘要： BackgroundHosts typically elicit diverse immune responses to the infection of various parasitic worms, with intestinal epithelial cells playing pivotal roles in detecting parasite invasion. Hymenolepis nana (H. nana) is a zoonotic parasitic worm that resides in the host's intestine. The contribution and underlying mechanisms of tuft cell-mediated immune reactions against H. nana remain *** study endeavors to examine the immune responses in the mouse intestine elicited by the adult H. nana and its excretory-secretory products (ESP). Ileal tissue alteration was detected using hematoxylin and eosin (H&E) staining, changes in the number of intestinal stem cells, goblet cells, tuft cells, and Paneth cells were detected by immunohistochemistry (IHC), immunofluorescence (IF), etc., and changes in the expression of type 2 cytokines and FOXM1 were detected by Western blotting (WB) or real-time quantitative polymerase chain reaction (RT-qPCR).ResultsThe presence of adult H. nana and its ESP enhanced the number of tuft cells and goblet cells while fostering the production of type 2 cytokines. Furthermore, the surge in Paneth cells and FOXM1 triggered by H. nana aids in maintaining intestinal stem cells homeostasis and proliferation. Notably, the FOXM1 inhibitor RCM-1 dampened intestinal stem cells differentiation and type 2 cytokines secretion, potentially impeding the host's capacity to eliminate H. *** adult H. nana and its ESP stimulate the immune responses in mice through tuft/interleukin (IL)-13 and FOXM1 signaling pathways and promote the elimination of H. nana from the host through the differentiation of intestinal stem cells into tuft cells, goblet cells, and Paneth cells, as well as the activation of type 2 immune responses. Meanwhile, RCM-1 inhibits the immune responses to H. nana in mice, thus affecting the excretion of H. nana by host.