IL-2 Stimulation Research Articles

Pulmonary vascular remodeling in Fra-2 transgenic mice is driven by type 2 inflammation and accompanied by pulmonary vascular hyperresponsiveness.

Lung vessel remodeling leads to increased pulmonary vascular resistance, causing pulmonary arterial hypertension (PAH), and consequently right ventricular hypertrophy and failure. In patients suffering from systemic sclerosis (SSc), PAH can occur and is a life-threatening complication. Dysregulation of immune processes plays a crucial role in pulmonary vascular remodeling, as has previously been shown in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH. Here, we investigate whether vascular remodeling in the Fra-2 TG model is driven by type 2 inflammation and is associated with vascular hyperresponsiveness, an important feature of PAH pathobiology. Basal pulmonary arterial pressure and pulmonary vascular responsiveness to hypoxic ventilation and serotonin were increased in isolated, perfused and ventilated lungs of Fra-2 TG mice compared to wild-type (WT) littermates. Similarly, contractile responses of isolated intrapulmonary arteries were elevated in Fra-2 TG mice. We also observed increased expression of contractile genes in Fra-2 overexpressing human pulmonary artery smooth muscle cells (PASMCs) with elevated intracellular calcium levels after IL-13 stimulation. These findings were corroborated by transcriptomic data highlighting dysregulation of vascular smooth muscle cell contraction and type 2 inflammation in Fra-2 TG mice. In vivo, type 2-specific anti-inflammatory treatment with IL-13 neutralizing antibodies improved vascular remodeling in Fra-2 TG mice, similar to corticosteroid treatment with budesonide. Our results underscore the importance of type 2 inflammation and its potential therapeutic value in PAH-associated pulmonary vascular remodeling and hyperresponsiveness in SSc-PAH.

Epstein-Barr Virus-Induced 3 Attributes to TLR7-Mediated Splenomegaly.

Epstein-Barr virus-induced 3 (EBI3) functions as a component of the heterodimer cytokine IL-27, which regulates innate and acquired immune responses. The expression of EBI3 gene is induced by Toll-like receptors (TLRs). Repeated treatment with imiquimod (IMQ), a TLR7 agonist, induces splenomegaly and cytopaenia due to increased splenic function. Although immune cell activation is speculated to play a role in chronic infection-mediated splenomegaly, the detailed mechanisms remain unknown. This study shows that IMQ treatment induces marked splenomegaly and severe bicytopaenia (anaemia and thrombocytopaenia) in wild-type mice. In IMQ-treated mice, myeloid cell populations in the spleen increased, and extramedullary haematopoiesis was observed. RNA-seq analysis revealed the upregulation of type I interferon (IFN)-related genes in the spleens of IMQ-treated mice. IMQ-induced pathological changes were partially mitigated by EBI3 deficiency. To investigate the mechanism of the improved phenotypes in the Ebi3 KO mice, we examined the involvement of IL-27, a heterodimer of EBI3 and IL-27p28. The expression of Il27a, which encodes IL-27p28, was increased in the spleen and peripheral blood by IMQ treatment. Furthermore, IL-27 stimulation upregulated type I IFN-related genes in bone marrow-derived macrophage cultures without type I IFN. These findings suggest that EBI3 deficiency mitigated IMQ-mediated pathological changes, presumably via a lack of IL-27 formation. Our study thus provides insights into the molecular mechanisms underlying chronic infection-mediated splenomegaly.

Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically

How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.

Transforming TGF-β suppression into IL-15 stimulation: Advancing engineered CAR-T therapy for solid tumors.

Transforming TGF-β suppression into IL-15 stimulation: Advancing engineered CAR-T therapy for solid tumors.

P0064 Investigating a pathogenic role for IL-18 in Inflammatory Bowel Disease beyond the classical type 1 immunity paradigm

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) are intestinal diseases driven by chronic reactivation of memory T helper (Thm) 1-like and Th17m cells, respectively. Disease remission remains difficult to achieve and maintain due to inter-patient heterogeneity in disease severity and underlying immune responses. Moreover, variations in the pathogenic Thm responses, the treatment target, are understudied. The proinflammatory cytokine IL-18 enhances IL-12-induced IFN-γ production by Th1 cells, as seen in Th1-driven inflammatory diseases. However, its potential pathogenic role in immune-mediated diseases, like CD and UC, is unclear. Upon investigating immune responses in therapy-naïve pediatric CD and UC patients, we detected increased IL-18 plasma concentrations that were correctable by therapy. We hypothesized that IL-18 plays a role in both CD and UC by stimulating Th1m but also Th17m cells, worsening disease. Methods We examined therapy-naïve pediatric CD and UC patient plasma proteomics (92 proteins, Proximity Extension Assay technology; CD: n=85, UC: n =31, control: n=25), circulating gut-homing Thm populations, transcriptomes of intestinal biopsies (CD: n=57, UC: n =21, control: n=12), and clinical disease parameters. Further, we assessed cytokine responses by healthy donor-derived Th1m and Th17m cells after IL-18 and IL-12 stimulation in vitro. Results Plasma IL-18 concentrations correlated to concentrations of Th1-associated proteins (IFN-γ, CXCL9, CXCL11, CXCL10, PDL1) in CD and UC. Interestingly, in UC patients, IL-18 concentrations also correlated to Th17-associated proteins (IL-12B, IL-17A, IL-24). In agreement, preliminary in vitro data showed that IL-18 + IL-12 stimulation increases IL-17A- and IFN-γ-secreting cell frequencies in CCR6+ Th17m cells. In CD, plasma IL-18 concentrations correlated to frequencies of circulating gut-homing CCR6+CXCR3+CCR4+ Th17m, a pathogenic population known to acquire Th1 features and IFN-γ production. Ileal and colonic mRNA expression of IL-18 pathway genes associated with degree of histological inflammation. Higher IL-18 plasma concentrations at diagnosis associated with moderate to severe disease and worse endoscopic scores in both CD and UC and greater disease extent in UC, suggesting a relationship between IL-18 and disease severity. In line with its preferential production in the ileum, plasma IL-18 concentrations were significantly higher in CD patients with ileal involvement compared to CD patients with colonic disease. Conclusion We identify IL-18 as a potential enhancer of both Th1-like and Th17-driven inflammation. High plasma IL-18 is detectable in subgroups of CD and UC patients, raising the question whether IL-18 acts on a specific disease-associated Thm cell population.

Inhibition of IL-4Rα reduces CCL26 in bronchial epithelial cells from COPD patients

BackgroundAnti-IL-4Rα monoclonal antibodies (mAb) improve lung function and decrease the number of exacerbations in patients with COPD type (T) 2 inflammation. However, the involvement of early innate immune responses underlying these treatment effects is not well known. We sought to understand the effect and mechanisms of IL-4Rα mAb treatment on bronchial epithelial cells from COPD patients under T2 inflammatory conditions with and without rhinoviral infection.MethodsPrimary bronchial epithelial cells (BECs) from healthy and COPD patients were grown at air–liquid interface (ALI) and stimulated with IL-4 or IL-13 cytokines in the presence of IL-4Rα mAb. Cells were infected with human rhinovirus 1B (HRV1B) and collected 24 h after infection. Anti-viral mediators (i.e., interferons (IFN) and pattern recognition receptors (PRR)), as well as chemokine and alarmin expression was measured by RT-qPCR and ELISA.ResultsTreatment with IL-4Rα mAb (100 nM) inhibited eotaxin-3 (CCL26) gene after IL-4/IL-13 induction (p<0.05) in COPD BECs. However, no significant changes in RV-induced IFN-β, PRRs or TSLP gene responses were observed with IL-4/IL-13 stimulation and IL-4Rα mAb treatment. Significant increase in MUC5AC gene expression was observed with both IL-4 and IL-13 stimulation, but it was not reduced with IL-4Rα treatment in BECs.ConclusionsInhibition of IL-4Rα reduced CCL26 levels without affecting anti-viral immune responses in bronchial epithelial cells from COPD patients. Inhibition of IL-4Rα reduced IL-4/IL-13 signaling without broadly suppressing the immune system, which might suggest that inhibition of the IL-4Rα pathways may prevent COPD exacerbations through reduction of eosinophil chemotaxis.

Regulation of fibronectin and collagens type I, III and VI by TNF-α, TGF-β, IL-13, and tofacitinib

Understanding how inflammatory cytokines influence profibrogenic wound healing responses in fibroblasts is important for understanding the pathogenesis of fibrosis. TNF-α and IL-13 are key cytokines in Th1 and Th2 immune responses, respectively, while TGF-β1 is the principal pro-fibrotic mediator. We show that 12-day fibroblast culture with TNF-α or IL-13 induces fibrogenesis, marked by progressively increasing type III and VI collagen formation, and that TGF-β1 co-stimulation amplifies these effects. Tofacitinib substantially reduced the formation of ECM proteins in response to IL-13, while fibrogenesis in response to TNF-α or TGF-β1 was marginally inhibited. The in vitro findings were supported by clinical observations in patients with active rheumatoid arthritis, which had elevated serum type III collagen formation, indicating ongoing fibrogenesis during inflammation. After 48–60 weeks of tofacitinib treatment, type III collagen degradation, aswell as formation, were significantly decreased compared to baseline, highlighting dual anti-inflammatory and anti-fibrogenic effects of tofacitinib. In contrast, other anti-inflammatory treatments including methotrexate, adalimumab and tocilizumab demonstrated anti-inflammatory effects only. Our results highlight fibro-inflammatory profiles associated with TNF-α or IL-13 stimulation, both alone and in combination with TGF-β1, and support the use of tofacitinib as an anti-fibrogenic treatment in chronic inflammatory conditions.

Dahuang chuanxiong decoction against contrast-induced nephropathy: Multi-omics, crosstalk between BNIP3-mediated mitophagy and IL-17 pathway.

Contrast-induced nephropathy (CIN), also known as contrast-induced acute kidney injury (CI-AKI), represents a prevalent form of hospital-acquired renal injury. However, the mechanisms underlying its pathogenesis remain unclear. Based on our previous research findings, the Dahuang Chuanxiong decoction (DCH), composed of Radix et Rhizoma Rhei (DH) and Rhizoma Chuanxiong (CX), has demonstrated efficacy for inhibiting CI-AKI by attenuating oxidative stress and apoptosis in renal tubular epithelial cells. Despite these findings, the detailed mechanisms underlying the renoprotective actions have not been thoroughly clarified. The objective of this study was to screen potential targets and signaling pathways involved in inhibition of CI-AKI by DCH using multi-omics analysis and to verify whether the renoprotective mechanism of DCH is related to these identified targets or pathways through in vivo and in vitro experiments. Initially, we identified the components of DCH using UPLC-Q-TOF-MS. Transcriptomics and proteomics, combined with experimental validation, were used to further elucidate the molecular mechanisms of the herbal pair in CI-AKI treatment. A CI-AKI rat model was established, and the expression levels of proteins related to mitophagy and the IL-17 signaling pathway were detected in renal tissues using immunofluorescence, immunohistochemistry, and western blotting analysis to elucidate the nephroprotective effects of DCH. Additionally, siRNA was used in the HK-2 cell model to investigate the crosstalk between the mitophagy and IL-17 signaling pathways and the impact on apoptosis when these pathways were inhibited. Multi-omics results revealed that the crucial signaling pathways involved were mitophagy, the MAPK signaling pathway, and the IL-17 signaling pathway. In vivo experiments indicated that contrast media (CM) led to an increase in AKI biomarkers, with upregulated expression of Parkin, BNIP3, IL-17, and p-NF-κB. Notably, pretreatment with DCH markedly reversed the expression of these proteins. Furthermore, we confirmed the importance of IL-17-mediated inflammation in the pathogenesis of CIN in vitro. We stimulated HK-2 cells with human IL-17 recombinant protein and observed an increase in the expression of p-NF-κB. Conversely, knockdown of IL-17 receptor A (IL-17RA) on the cell membrane reduced the expression of p-NF-κB and BNIP-3 under IL-17 stimulation. Additionally, the results revealed that BNIP3 knockdown reduced p-NF-κB production and alleviated the inflammation triggered by CM. The crosstalk between the two signaling pathways was initially explored. In conclusion, these findings suggested that DCH may exert ameliorative effects on CI-AKI through a multifaceted approach, including inhibition of BNIP3-mediated mitophagy and IL-17-mediated inflammation. This study elucidated the renoprotective mechanism of DCH through transcriptomics, proteomics, and experimental validation, providing evidence for the therapeutic potential of this agent in the clinical treatment of CI-AKI.

The Presence and Pathogenic Roles of M(IL-33 + IL-2) Macrophages in Allergic Airway Inflammation.

Macrophages, one of the most abundant immune cells in the lung, have drawn great attention in allergic asthma. Currently, most studies emphasize alternative activated (M2) polarization bias. However, macrophage function in allergic asthma is still controversial. Interleukin (IL)-9 contributes to the development and pathogenesis of allergic airway inflammation. We sought to investigate the IL-9-producing macrophage and its role in allergic asthma. The model of ovalbumin (OVA)-induced allergic airway inflammation was employed to evaluate IL-9 production in macrophages of lung tissues. We used 22 cytokines or stimuli to screen for IL-9-producing mouse macrophage subset invitro. Real-time PCR, flow cytometry, ELISA, and RNA-seq to explore the subset. Conditional IL-33 receptor knockout (Lyz-ST2KO) mice and cellular adoptive transfer experiment were used to characterize the potential roles of M(IL-33 + IL-2) in allergic asthma. We identified a unique pathogenic IL-9-producing macrophage in OVA-induced allergic airway inflammation. We found that only IL-33 significantly induced IL-9 production in mouse macrophages, and IL-2 collaborated with IL-33 to promote IL-9 production, referred to as M(IL-33 + IL-2). Importantly, human monocyte-derived macrophages produced IL-9 after IL-33 and IL-2 stimulation. Using Lyz-ST2KO mice and adoptive transfer of M(IL-33 + IL-2), we found that M(IL-33 + IL-2) significantly promoted pathogenesis in OVA-induced allergic airway inflammation. M(IL-33 + IL-2) has a distinctive gene expression profile with high expression of IL-9, IL-5, and IL-13 and its polarization is dependent on JAK2-STAT3-IRF1 pathway. The identification of M(IL-33 + IL-2) subset extends the diversity and heterogeneity of macrophage subsets and may offer novel therapeutic strategies for the treatment of allergic inflammation.

T-2 toxin induces senescence in human neuroblastoma SH-SY5Y cells by regulating the HIF-1α/p53/p21 pathway

The mechanisms by which T-2 toxin induces senescence in neurons, along with the involvement of hypoxia-inducible factor-1α (HIF-1α), remain poorly understood. Using human neuroblastoma SH-SY5Y cells as a model, T-2 toxin (6 nM, 1–48 h) induced senescence in SH-SY5Y cells, leading to cell cycle arrest. This was mediated by the upregulation of proteins involved in cell cycle regulation and stimulation of IL-6 and NF-κB expression. T-2 toxin rapidly triggered the expression of senescence-associated β-galactosidase, disrupted mitochondrial function, and altered the levels of Alzheimer’s disease-associated proteins (Tau, p-Tau, and APP). T-2 toxin also transiently elevated HIF-1α levels. Notably, HIF-1α regulated the expression of cell cycle inhibitory proteins (p16, p21, p53) and senescence-associated secretory phenotype factors (IL-8, IL-6, CCL2), along with the expression of senescence-associated β-galactosidase, thereby exacerbating T-2 toxin-induced cellular senescence. These findings underscore the vital role of HIF-1α in T-2 toxin-induced senescence in SH-SY5Y cells.

LPCAT1 reduces inflammatory response, apoptosis and barrier damage of nasal mucosal epithelial cells caused by allergic rhinitis through endoplasmic reticulum stress.

Allergic rhinitis (AR), common in children and adolescents, involves Lysophosphatidylcholine acyltransferase 1 (LPCAT1) catalyzing surfactant lipid biosynthesis and suppressing endoplasmic reticulum expression. However, the precise mechanism underlying the impact of LPCAT1 on epithelial cell damage in AR remains elusive. Hence, the present investigation elucidated the potential effect of LPCAT1 on epithelial cell damage in AR by inhibiting endoplasmic reticulum stress. To assess cell viability, CCK8 assay was employed. Additionally, western blotting was utilized to evaluate the expression of endoplasmic reticulum stress-associated proteins ATF6, CHOP, p-eIF2α, p-IRE1, and LPCAT1. Subsequently, an interference plasmid targeting LPCAT1 was constructed, and western blot analysis was conducted to determine interference level of LPCAT1. An ELISA assay was employed to quantify the concentrations of TNFα, IL-1β, IL-6, GM-CSF, and eotaxin. Additionally, flow cytometry and western blotting techniques were utilized to evaluate cellular apoptosis, whereas immunofluorescence staining was applied to detect the expression levels of ZO-1. Our findings indicated that IL-13 stimulation resulted in an elevated expression of ER stress proteins and LPCAT1 in nasal mucosal epithelial cells. Furthermore, LPCAT1 interference diminished the expression of inflammatory mediators, apoptosis markers, barrier disruption indicators, and ER stress proteins in IL-13-stimulated nasal mucosal epithelial cells. Further, by inhibiting ER stress, LPCAT1 interference diminished the expression of inflammatory factors, apoptosis, and barrier damage in nasal mucosal epithelial cells stimulated by IL-13. Concisely, LPCAT1 ameliorates AR-induced inflammation, apoptosis, and barrier impairment in nasal mucosal epithelial cells by modulating ER stress, implying its potential as a novel therapeutic target for AR.

271 Skin T cells in Atopic Dermatitis lack a profile indicative of IL-4 stimulation

271 Skin T cells in Atopic Dermatitis lack a profile indicative of IL-4 stimulation

The Role of Regulatory B Lymphocytes in Allergic Diseases.

Regulatory B cells (Bregs) are a key component in the regulation of the immune system. Their immunosuppressive function, which includes limiting the inflammatory cascade, occurs through interactions with other immune cells and the secretion of cytokines, primarily IL-10. As knowledge about B cells continues to expand, their diversity is becoming more recognized, with many subpopulations identified in both human and animal models. However, identifying specific transcription factors or markers that could definitively distinguish regulatory B cells remains a challenge. This review summarizes recent findings on the role of B regulatory cells in allergic diseases. In patients with bronchial asthma, atopic dermatitis, and food allergies, the number of regulatory B cells is reduced, and disease severity is inversely proportional to the quantity of these cells. Furthermore, in patients with atopic dermatitis, the ability of regulatory B cells to produce IL-10 in response to IL-6 stimulation is diminished. However, allergen immunotherapy has been shown to induce the formation of regulatory T cells as well as regulatory B cells. The success of future therapies based on B cells may depend on deepening our current understanding of their phenotypes, induction, differentiation, and function. Research in these areas is essential for understanding the mechanisms regulating Breg activity and for developing potential targeted therapies in the treatment of allergic diseases.

Horse Innate Immunity in the Control of Equine Infectious Anemia Virus Infection: A Preliminary Study.

The mechanisms of the innate immunity control of equine infectious anemia virus in horses are not yet widely described. Equine monocytes isolated from the peripheral blood of three Equine infectious anemia (EIA) seronegative horses were differentiated in vitro into macrophages that gave rise to mixed cell populations morphologically referable to M1 and M2 phenotypes. The addition of two equine recombinant cytokines and two EIA virus reference strains, Miami and Wyoming, induced a more specific cell differentiation, and as for other species, IFNγ and IL4 stimulation polarized horse macrophages respectively towards the M1 and the M2 phenotypes. Infection with EIAV reference strains resulted in a morphological transformation of macrophages compatible with the M1 differentiation pattern. All samples were also analyzed by molecular analyses for equine herpesviruses that could have acted as an interference and were found to be negative. The mRNA expression level of the pro-inflammatory genes MMP13 and IL6 in treated equine monocyte-derived macrophages (eMDMs) was evaluated by a SYBR® Green real-time PCR. In this study, MMP13 represented a reliable target gene to evaluate pro-inflammatory status of macrophages in horses because IFNγ and EIAV infection considerably increased its expression. A more in-depth study of the expression genes of both cytokine-induced and virus-induced markers of eMDM polarization may help us to understand whether these markers in horses are the same as those found in other animal species with similar pathways of innate immunity activation. The identified markers of each macrophage population would allow analysis of the differentiation profiles that could provide information on virus infectivity control in equid populations, envisioning their use in therapeutic strategies.

IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells

Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A+ CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39+CD103+ double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A– and NKG2A+ DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-β-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation.

LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis

ObjectivesAllergic rhinitis (AR) is a complex disorder with variable pathogenesis. Increasing evidence suggests that the LRRC8A is involved in maintaining cellular stability, regulating immune cell activation and function, and playing significant roles in inflammation. However, the involvement of LRRC8A in AR inflammation and its underlying mechanisms remain unclear.MethodsLRRC8A expression in AR patients, confirmed by qRT-PCR and Western blotting, was analyzed to investigate its relationship with the clinical characteristics of AR patients. In vitro, IL-13 stimulated HNEpCs to establish a Th2 inflammation model, with subsequent LRRC8A knockout or overexpression. NOX1/NOX4 inhibitor (GKT137831) and chloride channel inhibitor (DCPIB) were utilized to investigate AR development mechanisms during LRRC8A overexpression. An OVA-induced AR model with nasal mucosa LRRC8A knockdown confirmed LRRC8A's regulatory role in AR inflammation.ResultsLRRC8A mRNA and protein levels were significantly elevated in AR patients, positively correlating with NADPH oxidase subunits and Th2 inflammatory markers. In vitro, IL-13 stimulation of HNEpCs resulted in upregulation of LRRC8A and increased expression of NOX1, NOX4, and p22phox, along with mitochondrial dysfunction and NF-κB pathway activation. The knockout of LRRC8A reversed these effects. In nasal mucosal epithelial cells, DCPIB and GKT137831 completely blocked mitochondrial dysfunction caused by the overexpression of LRRC8A, which led to up-regulation of NOX1, NOX4, and p22phox. In vivo, knocking down LRRC8A reduced eosinophil infiltration, downregulated the expression of NOX1, NOX4, p22phox IL-4, IL-5, and IL-13, and decreased NF-κB pathway activation.ConclusionLRRC8A drives the upregulation of NOX1, NOX4, and p22phox, leading to ROS overproduction and mitochondrial dysfunction. It also activates NF-κB, ultimately leading to nasal mucosal epithelial inflammation. LRRC8A may be a potential target for the treatment of AR.

SOCS1 Inhibits IL-6-Induced CD155 Overexpression in Lung Adenocarcinoma.

CD155, also known as the poliovirus receptor (PVR), is a crucial molecule in the development and progression of cancer, as its overexpression favors immune evasion and resistance to immunotherapy. However, little is known about the mechanisms that regulate its overexpression. Proinflammatory factors produced by various cellular components of the tumor microenvironment (TME) have been associated with CD155 expression. We analyzed the effect of interleukin (IL)-6 on CD155 expression in lung adenocarcinoma. We found a positive relationship between mRNA and protein levels. This correlation was also observed in bioinformatics analysis and in biopsies and serum from patients with lung adenocarcinoma. Interestingly, lung adenocarcinoma cell lines expressing suppressor of cytokine signaling 1 (SOCS1) did not show increased CD155 levels upon IL-6 stimulation, and SOCS1 silencing reverted this effect. IL-6 and SOCS1 are critical regulators of CD155 expression in lung adenocarcinoma. Further basic and clinical studies are needed to define the role of these molecules during tumor development and to improve their clinical impact as biomarkers and targets for predicting the efficacy of immunotherapies. This study deepens the understanding of the intricate regulation of the immune checkpoints mediated by soluble factors and allows us to devise new ways to combine conventional treatments with the most innovative anticancer options.

Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse.

Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

MicroRNA-155-5p Differentially Regulates IL-13Rα1 and IL-13Rα2 Expression and Signaling Driving Abnormal Lung Epithelial Cell Phenotype in Severe Asthma.

MicroRNA (miR)-155-5p increases in innate and adaptive immune cells in response to IL-13 and is associated with the severity of asthma. However, little is known about its role in airway structural cells. Bronchial epithelial cells (BECs) isolated from healthy donors and patients with severe asthma were stimulated with IL-13. miR-155-5p expression and release were measured by real-time (RT)-PCR in BECs and in their derived exosomes. Modulation of miR-155-5p in BECs was performed using transfection of miR-155-5p inhibitor and mimic. IL-13 receptor α1 (IL-13Rα1), IL-13Rα2, MUC5AC, IL-8, and eotaxin-1 expression was measured by RT-PCR and Western blot analysis. The BEC repair process was assessed by a wound-healing assay. IL-13Rα1 and IL-13Rα2 expression and downstream pathways were evaluated by Western blot analysis. A dual luciferase assay was used to identify miR-155-5p target genes associated with IL-13R signaling. BECs from patients with severe asthma showed increased expression and exosomal release of miR-155-5p at baseline with amplification by IL-13 stimulation. BECs from patients with asthma expressed more IL-13Rα1 and less IL-13Rα2 than those from healthy donors, and IL-13Rα1 but not IL-13Rα2 induced miR-155-5p expression under IL-13 stimulation. miR-155-5p overexpression favored MUC5AC, IL-8, and Eotaxin-1 through the IL-13Rα1/SOCS1/STAT6 pathway while delaying the repair process by downregulating IL-13Rα2/MAPK14/c-Jun/c-fos signaling. The dual luciferase assay confirmed that miR-155-5p modulates both IL-13R pathways by directly targeting SOCS1, c-fos, and MAPK14. miR-155-5p is overexpressed in BECs from patients with severe asthma and regulates IL-13Rα1 and IL-13Rα2 expression and signaling, favoring expression of mucin- and eosinophil-related genes to the detriment of airway repair. These results show that miR-155-5p may contribute to airway epithelial cell dysfunction in patients with severe asthma.

Retinoic acid modulates peripheral blood helper innate lymphoid cell composition in vitro in patients with multiple sclerosis

This study investigates the frequency and numbers of circulating helper innate lymphoid cells (ILCs) in untreated relapsing-remitting multiple sclerosis (RRMS) patients, focusing on intracellular IL-10 and CCR6 expressions under IL-2, IL-33, and retinoic acid (RA) stimulation in vitro and their associations with clinical features in RRMS. In RRMS patients, ILC1 levels were notably higher upon IL-2 + IL-33 + RA stimulation, while ILC2 levels, particularly the c-Kit+ ILC2 and CCR6+ ILC2 subsets, were significantly lower compared to unstimulated conditions. Additionally, IL-10+ ILC1 levels were elevated. The ratios of IL-10+ ILC1/ILC1, c-Kit+ ILC2/c-Kit− ILC2, and CCR6+ ILC2/ILC2 were associated with the progression index (PI) in RRMS patients.