Interleukin-1 Receptor Research Articles

A synthetic chronogenetic gene circuit for programmed circadian drug delivery

Circadian medicine, the delivery of therapeutic interventions based on an individual’s daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading to inflammatory flares, with peak disease activity in the early morning. Using a combination of synthetic biology and tissue engineering, we developed circadian-based gene circuits, termed “chronogenetics”, that express a prescribed transgene downstream of the core clock gene promoter, Period2 (Per2). Gene circuits were transduced into induced pluripotent stem cells that were tissue-engineered into cartilage constructs. Our anti-inflammatory chronogenetic constructs produced therapeutic concentrations of interleukin-1 receptor antagonist in vitro. Once implanted in vivo, the constructs expressed circadian rhythms and entrained to daily light cycles, producing daily increases in biologic drug at the peak of Per2 expression. This approach represents the development of a cell-based chronogenetic therapy for various applications in circadian medicine.

IL-1β enhances susceptibility to atrial fibrillation in mice by acting through resident macrophages and promoting caspase-1 expression.

Atrial fibrillation (AF) is more prevalent in patients with elevated interleukin (IL)-1β levels. Here we show that daily administration of IL-1β for 15 days sensitizes mice to AF, leading to fibrosis, accumulation of β-pleated sheet proteins in the left atrium, and systemic inflammation, resembling the pathophysiological changes observed in patients with AF. IL-1β administration creates a positive feedback loop, dependent on the IL-1 receptor (IL-1R) activity in cardiac resident macrophages. This results in increased caspase-1 maturation in the left atrium and elevated Il1b and Casp1 transcription in atrial macrophages. IL-1β treatment accelerated action potential and Ca2+ restitution in the left atrium, leading to action-potential shortening. This, along with increased caspase-1 maturation and IL-1R signaling, was essential for inducing AF. Lack of IL-1R in macrophages, but not cardiomyocytes, prevented IL-1β-induced AF sensitivity. By depleting recruited macrophages or deleting IL-1R specifically in cardiac resident macrophages, we further demonstrate that IL-1β/IL-1R signaling in these resident macrophages is responsible for increased AF susceptibility. These findings offer insights into the therapeutic potential of targeting IL-1β/IL-1R signaling in patients with AF and emphasize the importance of recognizing different underlying causes in this patient group.

Role of Mirikizumab in the Treatment of Inflammatory Bowel Disease—From Bench to Bedside

Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin (IL)-23 to inhibit its interaction with the IL-23 receptor. IL-23 is a key cytokine involved in initiating and perpetuating the inflammatory cascade in inflammatory bowel disease (IBD). Mirikizumab is the first agent from the novel anti-IL-23p19 drug class to be licensed for ulcerative colitis and the first to present long-term endoscopic, histologic, symptomatic, and quality-of-life outcomes. More recently, the VIVID trial programme has led to the approval of mirikizumab in moderate to severe Crohn’s disease. This review explores the history of its development, discusses key immunopharmacological properties unique to the drug, and details the available clinical trials and real-world evidence supporting its use in IBD.

Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow

Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI.

IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control.

Although cytotoxic CD8+ T lymphocytes (CTLs) are essential for anti-tumour immunity, they are frequently dysfunctional in tumours1. Cytokines that sustain CTL activity are attractive for cancer immunotherapy, but avoiding inflammatory toxicity remains a challenge for their clinical use2. Here we show that expression of a CTL signature is strongly associated with IL27 expression in human and mouse tumours. In mice, IL-27 acts directly on tumour-specific CTLs to promote their persistence and effector function in the tumour microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of established tumours, drives an enhanced cytotoxic program in anti-tumour CTLs and synergizes with PD-L1 blockade. In patients with cancer who were treated with anti-PD-1/PD-L1 therapy, high expression of IL-27 correlates with a favourable clinical response, and IL-27 supports human CTL function during chronic antigen stimulation ex vivo. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumour T cell responses alone or in combination with PD-L1 blockade.

IL-23 Promotes γδT Cell Activity in Dry Eye Disease Progression.

Conjunctival-resident γδT cells, the predominant ocular source of interleukin-17A (IL-17A), play crucial roles in dry eye disease (DED) pathogenesis. The upstream regulators of these cells are unknown. This study evaluated the role of conjunctival IL-23 expression in mediating γδT cell generation and elucidated its contribution to dry eye inflammatory responses. Single-cell RNA sequencing (scRNA-seq) was used to identify and quantify conjunctival mRNA molecules in γδT cells in mice. The IL-23 level increased in wild-type (WT) and decreased in γδT-deficient (TCRδ-/-) mice after dry eye was induced via an intelligently controlled environmental system (ICES). Flow cytometry and transcriptome sequencing were used to investigate the impact of the changes in IL-23 expression on human γδT cells. The expression of the IL-23 receptor (IL-23R) was greater in γδT cells than in other conjunctival cell types, such as CD4+ T cells, CD8+ T cells and epithelial cells. An increase in IL-23 led to an increase in γδT cell density, which was proportional to dry eye severity. However, in the TCRδ-/- mice, the upregulation of IL-23 failed to increase the expression level of IL-17A and the severity of dry eye. Furthermore, increases in the expression of IL-23 and the number of γδT cells were evident in the ocular surface cells of patients who developed visual display terminal syndrome. An increase in conjunctival IL-23 expression contributes to the induction of the DED inflammatory response through interactions with its cognate receptor on γδT cells and the promotion of their proliferation. The findings of this study suggest that the suppression of IL-17A through the blockade of IL-23R activation may be a viable target for improving the management of inflammation in DED patients.

Radiotherapy-Associated Cellular Senescence and EMT Alterations Contribute to Distinct Disease Relapse Patterns in Locally Advanced Cervical Cancer.

A notable number of locally advanced cervical carcinoma (LACC) patients experience local or distant disease relapse following radiotherapy. The contribution of tumor microenvironment (TME) to tumor recurrence at different sites remains unclear. Here, single-nucleus RNA sequencing data from 28 pre- and on-treatment LACC samples from patients with different disease relapse patterns is analyzed. The findings revealed opposing alterations in the expression levels of the cellular senescence pathway after radiotherapy in patients with local and distant relapses. In contrast, an increase in the expression of the epithelial-mesenchymal transition module after radiotherapy in both relapse groups is observed. Cell-cell interactions, drug-target expression analyses in malignant cells after radiation, and multiplex immunofluorescence of tumor tissue identified interleukin-1 receptor type I (IL1R1) as a potential therapeutic target. It is demonstrated that combining the IL1R1 inhibitor anakinra with radiation can mitigate the effects of radiation on tumor cells. This study highlights the distinct roles of cellular senescence and EMT in tumor recurrence.

A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types

Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene “MANAscore” algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.

Transcriptome signature in the blood of neuromyelitis optica spectrum disorder under steroid tapering

BackgroundThe advent of biologics has significantly transformed treatment strategies for neuromyelitis optica spectrum disorder (NMOSD). However, there are no biomarkers that predict relapses associated with steroid tapering; therefore, it is critical to identify potential indicators of disease activity. In this study, we collected peripheral blood mononuclear cells (PBMCs) from NMOSD patients during steroid tapering and performed bulk RNA sequencing to analyze changes in immune dynamics caused by steroid reduction.MethodsPBMCs were collected at 3–5 timepoints from 10 NMOSD patients at our hospital (including one relapse case), and bulk RNA sequencing was performed. All patients were positive for anti-AQP4 antibodies and had no history of biologic use.ResultsIn one relapsed patient, gene groups with decreased expression at relapse were observed predominantly in monocytes, with upregulation in anti-inflammatory pathways such as IL-10, while the upregulated genes were related to interferon signaling. Moreover, after steroid tapering, in non-relapsed patients, genes with increased expression were enriched in inflammatory pathways, represented by interferon signaling, while genes with decreased expression were enriched in pathways related to IL-10 and glucocorticoid receptors. Weighted gene co-expression network analysis identified modules that correlated with steroid dosage, and the modules inversely correlated with steroid dosage were enriched in monocytes, with marked immune signature of interferon pathway.ConclusionThis study identified peripheral blood transcriptome signatures that could lead to the identification of clinically relevant NMOSD disease activity biomarkers, and further highlights the pivotal role of interferon and IL-10 signaling in NMOSD.

Novel strategies to manage CAR-Tcell toxicity.

The immune-related adverse events associated with chimeric antigen receptor (CAR)-Tcell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-Tcell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on-off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloidcell-intrinsic druggable targets and cellularengineering strategies to develop safer CAR-T cells.

Rational Identification of Ritonavir as IL-20 Receptor A Ligand Endowed with Antiproliferative Properties in Breast Cancer Cells

Targeting the tumor microenvironment (TME) is an attractive strategy for developing new drugs with anticancer activity against triple-negative breast cancer (TNBC). Interleukins (ILs) are key players in the TME cytokine network promoting cancer progression. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signalling in several cancers, including BC, in which IL-20RA is highly expressed, correlating with poor prognosis and influencing tumoral characteristics such as proliferation, cell death, invasiveness, and TME activity. Therefore, elucidating the role of the IL-20RA signalling pathway could form the basis for developing new therapeutic strategies. This study aimed to identify selective bioactive ligands able to affect IL-20RA activity. Virtual screening of over 310,000 compounds from both the DrugBank and ZINC15 databases identified four potential hit compounds tested for their anticancer activity against TNBC in vitro cell lines. Notably, Ritonavir, a well-known Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitor, significantly inhibited cell proliferation (about 40% at 50 µM, p < 0.001). IL-20 preincubation counteracted Ritonavir’s cytostatic effect while IL-20RA knockdown restored proliferation in Ritonavir-treated TNBC cells. In conclusion, these findings demonstrated that Ritonavir reduced TNBC cell proliferation through IL-20RA activity modulation, suggesting its potential repurposing as a therapeutic agent for TNBC management.

Interleukin 29 is a novel antiangiogenic factor in angiogenesis.

Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Despite the importance of Interleukin 29 (IL-29), a newly identified cytokine of type III interferon family, its role in angiogenesis remains unknown. We aimed to elucidate IL-29's impact on angiogenesis under both and physiological and pathological conditions. We employed various assays to evaluate IL-29's effect on proliferation, apoptosis, migration and tube formation of human umbilical vein endothelial cells (HUVEC) in vitro. IL-29's angiogenic effect was assessed using mouse aortic rings ex vivo, and oxygen-induced retinopathy (OIR) mouse model in vivo. Signaling pathways possibly involved in IL-29-induced angiogenesis were investigated by Western blot. Finally, IL-29's impact on tube formation was blocked by inhibiting IL-29/interleukin 10 receptor 2 (IL-10R2) binding. IL-29 treatment inhibited endothelial cell migration, tube formation and vessel sprouting, without affecting proliferation or apoptosis. Notably, IL-29 (100ng/ml) attenuated vessel growth in pathological angiogenesis in OIR mice, accompanied by decreased expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α). Mechanistically, IL-29 activated Stat3 signaling pathway, and blocking IL-29/IL-10R2 binding remarkably reversed IL-29's anti-angiogenic effect on tube formation. Our findings demonstrated that IL-29, at a relative low concentration, modulates angiogenesis in both physiological and pathological contexts. Targeting IL-29 or its receptor IL-10R2 offers a promising strategy for angiogenesis regulation in various conditions.

Identification of potential geosmin-binding proteins in grass carp gill based on affinity responsive target stability and tandem mass tag proteomics.

The escalating issue of water pollution, especially the accumulation of organic off-flavor pollutants, poses significant challenges. Geosmin, a typical off-flavor compound in aquatic environments, not only compromises the quality of aquatic products but also deters consumers. Its impact extends to aquatic organisms, with current research focusing on dose-response and ecotoxicity, while neglecting the molecular-level study of geosmin-binding proteins. This study employs an integrated approach combing affinity-responsive target stability in vitro, tandem mass tag proteomics in vivo, and molecular docking to identify geosmin-binding proteins in the gill tissue of grass carp (Ctenopharyngodon idella). ARTS analysis identified 56 proteins, predominantly membrane-associated proteins, such as catenin beta-1, annexin, and integrin beta. Proteomic analysis revealed 256 differentially expressed proteins in geosmin-exposure group, with 18 common proteins screened by in vivo and in vitro methods. Among these, annexin, cathepsin D, and interleukin-1 receptors were highlighted as potential geosmin targets, with annexin demonstrating the highest binding affinity in silico. This study provides a robust protocol integrating in vivo, in vitro, and in silico approaches to elucidate geosmin's target proteins in grass carp gill tissue, advancing our understanding of pollutant-biological interactions and enhancing environmental risk assessment accuracy.

IL-15/IL-15Rα-secreting bioengineered adipocytes reactivate NK/CD8+ T cells in ovarian and colon cancer ascites.

Malignant ascites (MA) presents a complex clinical challenge, linked inextricably to poor prognosis, chemoresistance, and metastasis of peritoneal carcinomatosis (PC). However, standard therapeutic approaches for managing or preventing MA secondary to PC remain unavailable. Here we display that a bioengineered adipocyte, encapsulating long-chain fatty acids and concurrently secreting IL-15 and IL-15 receptor α (IL-15Rα), markedly extends the half-life and bioactivity of IL-15. The bioengineered adipocyte consists of an IL-15-P2A-IL-15Rα-T2A-mCherry cDNA sequence stable transfected 3T3-F442A preadipocyte cell line and dcosahexaenoic acid (DHA) are simultaneously encapsulated in the lipid droplets of mature adipocytes, which release it into the MA upon tumor cell-triggered lipolysis. We demonstrate that the bioengineered adipocytes led to specific expansion and activation of NK/CD8+ T cells response to the IL-15/IL-15Rα complex in MA, thereby reversing immuno-suppressive phenotype of ascitic immune cells and enabling them to recognize and attack cancer cells. This synergistic therapeutic strategy exhibits therapeutical manipulation of the ascitic immune cells, restores normal immune functioning, and suppresses cancer cell metastasis and tumor growth in ovarian cancer and colon cancer, all while minimizing systemic adverse effects.

Food Intolerance and Allergy: Do They Have an Etiological Role in Idiopathic Granulomatous Mastitis?

Background/Objectives: Despite its long-standing recognition, the etiopathogenesis of idiopathic granulomatous mastitis (IGM) remains poorly understood. This study aims to investigate the relationship between IGM and food intolerance, allergies, and immunological factors to shed light on its etiology. Materials and Methods: This case–control study included 32 patients with IGM and 32 healthy women. In order to examine their potential relevance to allergy and immunology, serum interleukin (IL)-4, IL-4 receptor, histamine, and histamine-releasing factor (HRF) were measured by ELISA. Furthermore, serum IgG antibodies against specific food allergens were measured to evaluate food intolerance. Results: The patient group exhibited significantly higher intolerance values for lentils and curry compared to the control group (p = 0.023 and p = 0.012, respectively). Histamine (p < 0.001) and IL-4 (p = 0.003) levels were elevated in IGM patients compared to the control group, while HRF and IL-4R outcomes did not show any significant differences (p > 0.05). Conclusions: Elevated histamine and IL-4 levels may suggest the involvement of allergy and immunological factors in IGM’s etiopathogenesis. The integration of anti-histamine medications for IGM patients with elevated histamine levels could provide an alternative therapeutic strategy.

Potentiating CAR-T cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal.

The immunosuppressive tumor microenvironment represents a key challenge for chimeric antigen receptor (CAR) Tcells in solid tumors and includes the production of the inhibitory cytokine transforming growth factor β (TGF-β), which limits CAR-T cell persistence and function. Current strategies involving the blockade of TGF-β signaling have little benefit for solid tumor treatment. Here, we demonstrate a novel inverted cytokine receptor (ICR)-modified CAR-T cell strategy not only TGF-β signal blockade but also antitumor efficacy enhancement. The newly designed Tcells carry an ICR construct that fuses the TGF-β receptor II extracellular domain to the interleukin-15 (IL-15) receptor α cytoplasmic domain (named TB15) and is directed to the tumor antigen epidermal growth factor receptor by a CAR construct. In mice with high TGF-β solid tumors, our signal-inverted CAR/TB15 Tcells effectively treat tumors by blocking TGF-β and repurposing IL-15 stimulative signaling, resulting in enhanced CAR-T cell persistence and function. As a proof of concept, our study results extend synthetic receptor signaling beyond CAR-directed killing, which could endow adoptively transferred Tcells with new functions that overcome major barriers in the treatment of solid tumors by using a chimeric ICR.

Multi-omics elucidates the kidney damage caused by aquatic Cu via the gut-kidney axis in ducks.

Copper (Cu) is an essential trace element for biological growth and development. Excessive intake of Cu exists harmful effects on organisms. However, whether excessive Cu intake induces kidney function damage by gut microbiota regulation remains unclear. Ducks are important species of waterfowl that are often exposed to Cu contamination in water sources. In this study, we aim to elucidate the effects of Cu exposure on renal inflammation through the gut-kidney axis in ducks. The ducks were gavaged with different doses of CuSO4 (0, 100, and 200 mg/kg body weight) for 4 weeks. Results indicate that Cu exposure causes pathological damage to the kidney, with a significant increase in the levels of TNFα, IL-6, and IL-1β in both serum and renal tissue. 16S rDNA analysis revealed that the relative abundances of Candidatus_Saccharimonas and Bacteroides were significantly reduced in the Cu-induced group. Transcriptomic analysis of kidney tissue reveals that following Cu exposure, 30 genes show significant differential expression. GO and KEGG enrichment analyses were most involved in Interleukin-1 Receptor Activity, Taurine and hypotaurine metabolism, Nitrogen metabolism, and Proximal tubule bicarbonate reclamation. Metabolomic analysis revealed that 28 metabolites are present in both kidney tissue and cecal contents. Correlation analysis revealed a strong correlation among 5 common metabolites: Aminoglutethimide, Boscalid, Dantrolene, Cer[ns] d34:1, and Stearidonic acid. In the cecum, these five metabolites are closely associated with 26 intestinal microorganisms, including Bacteroides, Candidatus_Saccharimonas, and Colidextribacter. In the kidney, apart from Stearidonic acid, the other four metabolites are closely correlated with genes such as FOS, and IL1RL1. Overall, our study indicates that excessive Cu induces significant kidney inflammation, the metabolites alteration and gut microbiota disorders. These findings shed light on the underlying mechanisms of Cu-induced kidney damage via the indirect pathway of the gut-kidney axis.

A spectrum of neurological diseases with elevated cerebrospinal fluid adenosine deaminase levels.

This study aimed to investigate cerebrospinal fluid (CSF) adenosine deaminase (ADA) levels in various neurological disorders and examine the relationships between CSF ADA levels and immunological parameters. Overall, 276 patients whose CSF ADA levels were measured for suspected tuberculous meningitis (TBM) were evaluated. Data on baseline characteristics, final diagnoses, CSF ADA levels, and other laboratory parameters were collected. Thereafter, CSF ADA levels were compared based on final diagnoses, and correlations between CSF ADA levels and other CSF and blood laboratory parameters were evaluated. Five diseases exhibited a significant increase in CSF ADA levels relative to the noninflammatory disease control group (n=40): (1) TBM (n=15, p<0.0001), (2) fungal meningitis (n=7, p=0.0400), (3) autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A, n=7, p<0.0001), (4) neurosarcoidosis (n=7, p=0.0028), and (5) lymphoproliferative disorders (n=18, p=0.0001). Strong positive correlations were observed between CSF ADA and CSF parameters, including soluble IL2 receptor (rs=0.7566, p<0.0001), albumin (rs=0.6693, p<0.0001), lactate dehydrogenase (rs=0.6452, p<0.0001), white blood cell count (rs=0.6035, p<0.0001), protein (rs=0.6334, p<0.0001), and lymphocytes (rs=0.5954, p<0.0001). CSF ADA levels were elevated in various inflammatory neurological diseases, especially in TBM, fungal meningitis, GFAP-A, neurosarcoidosis, and lymphoproliferative disorders. CSF ADA levels may reflect T-cell hyperactivation in the central nervous system.

Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer.

Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body's anti-cancer defense, and chimeric antigen receptor (CAR)-NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.

Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin.