Interleukin-1 Receptor Research Articles

Interleukin 8-CXCR2 mediated neutrophil extracellular trap (NET) formation in biliary atresia associated with NET-Induced stellate cell activation.

Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and if NETs induce stellate cell activation. BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, & IL-8 were quantified by ELISA for plasma and by immunohistochemistry (IHC) for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by RT-qPCR, ELISA and FACS. Liver neutrophils, NETs and plasma elastase, NETs and IL-8 were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. IHC identified increased NET expression of pro-fibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation, based on increased ACTA2 & COL1A1 mRNA, collagen protein and cell surface expression of actin, collagen1A and PDGFRβ. BA patients have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.

Evaluating the feasibility of using whole blood gene expression profiles to identify novel targets in canine septic peritonitis.

To assess gene expression profiles in canine whole blood with and without septic peritonitis to assess workflow feasibility and identify potential blood biomarkers that could be further investigated in future studies. This study enrolled 6 dogs with cytologically confirmed septic peritonitis of any cause and 6 healthy dogs. All dogs had a CBC and biochemistry performed. The dogs with septic peritonitis also had point-of-care lactate and blood oxygen saturation measured for acute patient physiologic and laboratory evaluation score calculation. All dogs then had 2.5 mL of whole blood collected and placed into an RNA stabilization tube, which was processed using a commercial assay based on the hybridization of fluorescent probes for transcript quantification. Quality control, normalization, and data visualization were performed. Raw counts were exported, and differential expression was performed. The evaluation of canine whole blood expression profiles was confirmed to be feasible. Differential expression analysis of septic and nonseptic dogs demonstrated distinct gene expression profile signatures. Five genes of interest were upregulated in septic whole blood including matrix metallopeptidase 9, IL-1 receptor type 2, proliferating cell nuclear antigen, phosphatidylinositol 3-kinase catalytic-γ, and cluster of differentiation 55. The study and associated workflow were feasible and can be scaled in confirmatory studies. Future studies are now proposed to further validate the increased expression of putative biomarkers in a larger cohort of canine septic peritonitis patients with more relevant comparator control cohorts.

Interleukin-22 promotes endometrial carcinoma cell proliferation and cycle progression via ERK1/2 and p38 activation.

Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors, but its underlying pathogenic mechanisms are largely obscure. Interleukin-22 (IL-22), one cytokine in the tumor immune microenvironment, was reported to be associated with carcinoma progression. Here, we aimed to investigate the regulation of IL-22 in endometrial carcinoma. Enzyme-linked immunosorbent assay (ELISA) analysis of IL-22 was done in 27 controls and 51 patients with EC. We examined the proliferative potential, cycle progression, and signaling pathways modulated by IL-22 in EC cells. Western blot analysis was performed to investigate the expression of proliferative and cycle-related proteins in EC cells. The effect of IL-22 mediated by interleukin-22 receptor alpha 1 (IL-22RA1) was examined using cell transfection with small interfering RNA (siRNA). In addition, a xenograft tumor model was performed to assess the effect of IL-22 in vivo. We demonstrated significant up-regulation of serum IL-22 concentrations in EC patients (42.59 ± 23.72pg/mL) compared to the control group (27.47 ± 8.29pg/mL). High levels of IL-22 concentrations appear to correlate with malignant clinicopathological features of EC. Treatment with IL-22 promoted cell proliferation and G1/S phase progression in Ishikawa and HEC-1B cells. Western blot analysis revealed that c-Myc, cyclin E1, cyclin-dependent kinase (CDK)2, cyclin D1, CDK4, CDK6, p-extracellular signal-regulated kinase1/2 (p-ERK1/2), and p-p38 were highly expressed in EC cells exposed to IL-22. Moreover, in the EC mice model, we found that giving exogenous IL-22 increased tumor volume and weight. Immunohistochemistry showed that intra-tumor Ki-67 expression was up-regulated upon IL-22 treatment. The IL-22-mediated changes in cell proliferation, cycle progression, and protein expression can be effectively inhibited by the ERK1/2 inhibitor U0126 and the p38 inhibitor SB202190. In addition, the role of IL-22 in EC is receptor-dependent. Our findings suggest that IL-22 promotes endometrial carcinoma cell proliferation and G1/S phase progression by activating ERK1/2 and p38 signaling. Therefore, IL-22 may represent a potential therapeutic target for the treatment of endometrial carcinoma.

Biologic drugs induced vitiligo: case reports and review of literature

Biological drugs are extensively used to treat various inflammatory diseases, including psoriasis, atopic dermatitis (AD), and rheumatoid arthritis. While generally effective and safe, these therapies have been increasingly associated with secondary development of vitiligo, especially with anti-TNF α and anti-IL17 drugs. Dupilumab, an IL-4 receptor alpha antagonist used in moderate to severe AD, rarely induces vitiligo. This study reports two cases of new-onset vitiligo following dupilumab treatment for AD. The first case involves an 80-year-old male who developed vitiligo patches appeared on the chest, back, and lower limbs after 2 months of dupilumab therapy. Despite discontinuation of dupilumab, the vitiligo did not regress. The second case describes a 14-year-old female who experienced depigmentation on her forehead one month into dupilumab treatment, with partial improvement of vitiligo lesions over time despite continued therapy. This phenomenon may be due to dupilumab blocking type 2 inflammation, disrupting normal skin homeostasis, and exacerbating type 1 inflammation. These cases, supplemented with a literature review, highlight the potential for biologic drug-induced vitiligo and underscore the need for awareness of such adverse events in clinical practice. The mechanisms underlying this phenomenon likely involve disruption of the Th1/Th2/Th17 cytokine balance, suggesting that targeted therapies may inadvertently exacerbate type 1 inflammation, leading to vitiligo. With the rising use of biologics, clinicians should carefully consider the risk of vitiligo when prescribing these treatments.

Foxp3 + Treg-derived IL-10 promotes colorectal cancer-derived lung metastasis

The lung is one of the most frequently metastasized organs from various cancer entities, especially colorectal cancer (CRC). The occurrence of lung metastasis correlates with worse prognosis in CRC patients. Here, we aimed to investigate the role of IL-10 in lung metastasis development and identify the cellular source and target cells of IL-10 during lung metastatic establishment. To induce lung metastasis in mice, we injected MC38 murine colon cancer cells intravenously. Mice with Il10-deficiency were used to test the role of IL-10. The lung metastatic burden was assessed both macroscopically and histologically. IL-10- and Foxp3-reporter mice were employed to identify the cellular source and target cells of IL-10 in lung metastasis using flow cytometry. These findings were further confirmed using mice with cell-specific deletion of Il10- and IL-10 receptor (Il10ra). Interestingly, Il10 ablation led to reduced lung metastasis formation, suggesting a pathogenic role of IL-10 in lung metastasis. Moreover, using reporter mice, we identified Foxp3 + regulatory T cells (Tregs) as the predominant cellular source of IL-10 in lung metastasis. Accordingly, Foxp3 + Treg-specific deletion of Il10 resulted in decreased lung metastasis formation. In terms of target cells, myeloid cells and Foxp3 + Tregs expressed high IL-10Ra levels. Indeed, IL-10 signaling blockade in these two immune cell populations resulted in reduced lung metastatic burden. In conclusion, Foxp3 + Treg-derived IL-10 was found to act on Foxp3 + Tregs and myeloid cells, thereby promoting lung metastasis formation. These findings provide insights into lung metastasis-related immunity and establish the groundwork for optimizing metastasis-targeting immunotherapies through targeting of IL-10 as a novel therapeutic strategy.

Assessment of the Monocyte Subpopulations and M1/M2 Macrophage Ratio in Concentrated Bone Marrow Aspirate.

The purpose of this study was to determine the M1/M2 macrophage ratio in concentrated bone marrow aspirate (cBMA) in patients undergoing surgical intervention augmented with cBMA for osteochondral lesions of the talus (OLTs). Samples of peripheral blood (PB), bone marrow aspirate (BMA), and cBMA were collected during the procedure. The samples were analyzed by automated cell counting and multicolor fluorescence-activated cell sorting with specific antibodies recognizing monocytes (CD14+ CD16+) and the M1 (CD86+) and M2 (CD163+CD206+) populations within that monocyte population. Cytokine concentrations within the samples were evaluated with enzyme-linked immunosorbent assay (ELISA). The composition of cBMA was compared between 2 commercially available BMA concentration systems. Thirty-eight patients with a mean age of 43.2 ± 10.1 years old undergoing a surgical procedure for the treatment of OLTs involving the use of cBMA were included. cBMA had a mean fold increase of 4.7 for all white blood cells, 6.1 for monocytes, 7.9 for lymphocytes, 2.4 for neutrophils, and 9.6 for platelets when compared to BMA. The mean M1/M2 ratio for PB, BMA, and cBMA was 15.2 ± 12.0, 20.8 ± 13.3, and 22.1 ± 16.0, respectively. There was a statistically significant higher concentration of interleukin-1 receptor antagonist (IL-1Ra) in the cBMA sample (8243.3 ± 14,837.4 pg/mL) compared to both BMA (3143.0 ± 2218.5 pg/mL) and PB (1847.5 ± 1520.4 pg/mL) samples. The IL-1Ra/IL-1β ratio for PB, BMA, and cBMA was 790.6 ± 581.9, 764.7 ± 675.2, and 235.7 ± 192.1, respectively. There was no difference in the cBMA M1/M2 ratio (19.0 ± 11.1 vs 24.0 ± 18.3) between the Magellan (Isto Biologics, Hopkinton, Massachusetts) and Angel systems (Arthrex Inc, Naples, Florida). This prospective study found that the M1/M2 ratio in cBMA was 22.1 ± 16.0, with significant patient to patient variation observed. Overall, there was no statistically significant difference in the M1/M2 ratio across PB, BMA, and cBMA samples. This is the first study to characterize the macrophage subpopulation within cBMA, which may have significant clinical implications in future studies.

The Comparative Effects of Anakinra and Tocilizumab on Inflammation and Cerebral Vasospasm in an Experimental Subarachnoid Hemorrhage Model

Objective: Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular condition that triggers a robust inflammatory response and cerebral vasospasm. This study aimed to evaluate the effects of anakinra, an interleukin-1 receptor antagonist, and tocilizumab, an interleukin-6 receptor antagonist, on inflammation and vasospasm in an experimental rat SAH model. Methods: Forty male Sprague Dawley rats (200–250 g) were randomly assigned to five groups: control, SAH, SAH + anakinra (ANA), SAH + tocilizumab (TCZ), and SAH + anakinra + tocilizumab (ANA+TCZ). SAH was induced by injecting non-heparinized arterial blood into the cisterna magna. Treatment groups received anakinra (50 mg/kg twice daily), tocilizumab (8 mg/kg once daily), or their combination for three days. Blood and cerebrospinal fluid (CSF) samples were analyzed for inflammatory markers (IL-1, IL-6, TNF-α, CRP), and histopathological evaluations were conducted to assess vasospasm and apoptosis. Results: SAH significantly increased pro-inflammatory cytokines (IL-1, IL-6, TNF-α, CRP) and fibrinogen levels in serum and CSF while reducing the basilar artery lumen diameter (p < 0.001). Anakinra and tocilizumab treatments significantly reduced inflammatory markers and vasospasm severity compared to the SAH group (p < 0.05). Combination therapy was more effective in reducing inflammation and vasospasm than either treatment alone (p < 0.05). Anakinra showed a stronger effect on IL-1 reduction, while tocilizumab was more effective in lowering IL-6 levels. The ANA+TCZ group exhibited a significant decrease in caspase activity, indicating reduced apoptosis (p < 0.05). Conclusions: Anakinra and tocilizumab effectively mitigated inflammation and vasospasm in an experimental SAH model, with combination therapy showing superior efficacy. These findings suggest that targeting both IL-1 and IL-6 pathways may be a promising therapeutic strategy for managing SAH complications. Further studies are warranted to evaluate long-term outcomes and clinical implications.

Sonodynamic Nano-LYTACs Reverse Tumor Immunosuppressive Microenvironment for Cancer Immunotherapy.

Extracellular and transmembrane proteins, which account for the products of approximately 40% of all protein-encoding genes in tumors, play a crucial role in shaping the tumor immunosuppressive microenvironment (TIME). While protein degradation therapy has been applied to membrane proteins of cancer cells, it has rarely been extended to immune cells. We herein report a polymeric nanolysosome targeting chimera (nano-LYTAC) that undergoes membrane protein degradation on M2 macrophages and generates a sonodynamic effect for combinational cancer immunotherapy. Nano-LYTAC is found to have higher degradation efficacy to the interleukin 4 receptor (IL-4R) compared to traditional inhibitors. More importantly, it is revealed that the effect of nano-LYTAC on the function of the M2 macrophage is concentration-dependent: downregulating CD206 expression and interleukin 10 (IL-10) secretion from M2 macrophages at low concentration, while triggering their apoptosis at high concentration. Moreover, nano-LYTAC is found to possess long tumor retention (>48 h), allowing for multiple sonodynamic treatments with a single dose. Such a synergistic sonodynamic immunotherapy mediated by nano-LYTAC effectively reprograms the TIME via inhibiting the functions of M2 macrophages and regulatory T cells (Tregs), as well as promoting the maturation of dendritic cells (DCs) and tumor infiltration of T effector cells (Teffs), completely suppressing tumor growth, inhibiting pulmonary metastasis, and preventing recurrence under preclinical animal models.

Low-grade systemic inflammation, but not neuroinflammation, is associated with 12-month postoperative outcome after total hip arthroplasty in patients with painful osteoarthritis.

Better prediction of outcome after total hip arthroplasty (THA) is warranted. Systemic inflammation and central neuroinflammation are possibly involved in progression of osteoarthritis and pain. We explored whether inflammatory biomarkers in blood and cerebrospinal fluid (CSF) were associated with clinical outcome, and baseline pain or disability, 12 months after THA. A total of 50 patients from the Danish Pain Research Biobank (DANPAIN-Biobank) between January and June 2018 were included. Postoperative outcome was assessed as change in Oxford Hip Score (OHS) from baseline to 12 months after THA, pain was assessed on a numerical rating scale, and disability using the Pain Disability Index. Multiple regression models for each clinical outcome were included for biomarkers in blood and CSF, respectively, including age, sex, BMI, and Kellgren-Lawrence score. Change in OHS was associated with blood concentrations of tumour necrosis factor (TNF), interleukin-8 (IL-8), interleukin-6 receptor (IL-6R), glycoprotein 130 (gp130), and IL-1β (R2 = 0.28, p = 0.006), but not with CSF biomarkers. Baseline pain was associated with blood concentrations of lymphotoxin alpha (LTα), TNFR1, TNFR2, and IL-6R (R2 = 0.37, p < 0.001) and CSF concentrations of TNFR1, TNFR2, IL-6, IL-6R, and IL-1Ra (R2 = 0.40, p = 0.001). Baseline disability was associated with blood concentrations of TNF, LTα, IL-8, IL-6, and IL-1α (R2 = 0.53, p < 0.001) and CSF concentrations of gp130, TNF, and IL-1β (R2 = 0.26, p = 0.002). Thus, preoperative systemic low-grade inflammation predicted 12-month postoperative outcome after THA, and was associated with preoperative pain and disability. This study highlights the importance of systemic inflammation in osteoarthritis, and presents a possible path for better patient selection for THA in the future. Preoperative central neuroinflammation was associated with preoperative pain and disability, but not change in OHS after THA.

Assessment of Inflammatory Biomarkers and Incident Atrial Fibrillation in Older Adults.

Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07-1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01-1.09); white blood cell count, HR, 1.18 (95% CI, 1.04-1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05-1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05-1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07-1.26). Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.

Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs.

Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4+ T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads. Screening a diverse library of suppression programs, we observed the strongest suppression of cytotoxic T cell attack by the production of both anti-inflammatory factors (interleukin-10, transforming growth factor-β1, programmed death ligand 1) and sinks for proinflammatory cytokines (interleukin-2 receptor subunit CD25). Engineered cells with bespoke regulatory programs protected tissues from immune attack without systemic suppression. Synthetic suppressor T cells protected transplanted beta cell organoids from cytotoxic T cells. They also protected specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reaction. Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision.

Targeting interleukin-6 pathways in giant cell arteritis management: A narrative review of evidence.

Giant cell arteritis (GCA) is a chronic inflammatory vasculitis with a significant impact on vascular and patient health. It may present with non-specific symptoms and can lead to severe complications if not managed effectively. This narrative review explores the treatment of GCA with interleukin-6 pathway inhibitors, focusing on key studies from selected databases published between 2018 and 2024. The findings reveal that the current treatment primarily involves glucocorticoids (GCs), but their long-term use is associated with adverse effects. Targeting the interleukin-6 (IL-6) pathway offers therapeutic benefits by reducing inflammation and sparing GC use. Tocilizumab, a humanized immunoglobulin G1κ monoclonal antibody that blocks the IL-6 receptor, has demonstrated efficacy in achieving sustained remission and improving quality of life in people with GCA. However, challenges remain in understanding the optimal duration of therapy, managing relapse upon discontinuation, and addressing long-term structural vascular outcomes. Additional research is needed to further elucidate the complex pathogenesis of GCA and to optimize treatment strategies to achieve sustained remission both clinically and histologically while minimizing adverse effects. This review provides a comprehensive overview of the evidence of IL-6 inhibition in GCA management, highlighting both its therapeutic benefits and the challenges associated with its use.

IL-33-experienced group 2 innate lymphoid cells in the lung are poised to enhance type 2 inflammation selectively in adult female mice

While Th2 adaptive immunity has long been considered to orchestrate type 2 inflammation in the allergic lung, group 2 innate lymphoid cells (ILC2s), with the ability to produce a similar profile of type 2 cytokines, likely participate in lung inflammation in allergic asthma. ILC2s are also implicated in sex disparities in asthma, supported by data from murine models showing they are inhibited by male sex hormones. Moreover, larger numbers of ILC2s are present in the lungs of female mice and are correlated with greater type 2 inflammation. Lung ILC2s exhibit intriguing memory-like responses, though whether these differ in males and females does not appear to have been addressed. We have examined type 2 lung inflammation in adult male and female Balb/c mice following delivery of IL-33 to the lung. While the number of ILC2s was elevated equally in males and females four weeks after exposure to IL-33, ILC2s from female mice expressed higher levels of ST2, the IL-33 cognate receptor subunit, and a larger proportion of ILC2s from females expressed the IL-25 receptor (IL-25R), which has previously been linked to memory-like ILC2 responses in mice. Our data show that the subset of ILC2s expressing IL-25R, upon activation, was more likely to produce IL-5 and IL-13. Moreover, STAT6 was absolutely required for enhanced responsiveness in this model system. Altogether, our data show that enhanced type 2 inflammation in females is linked to durable changes in ILC2 subsets with the ability to respond more robustly, in a STAT6-dependent manner, upon secondary activation by innate epithelial-derived cytokines.

Group 2 innate lymphoid cells are a non-redundant source of interleukin-5 required for development and function of murine B1 cells

Tissue-resident immune cells, such as innate lymphoid cells, mediate protective or detrimental immune responses at barrier surfaces. Upon activation by stromal or epithelial cell-derived alarmins, group 2 innate lymphoid cells (ILC2s) are a rapid source of type 2 cytokines, such as IL-5. However, due to the overlap in effector functions, it remains unresolved whether ILC2s are an essential component of the type 2 response or whether their function can be compensated by other cells, such as T cells. Here we show a non-redundant role of ILC2s in supporting the development and function of B1 cells. We demonstrate that B1 cells fail to develop properly in the absence of ILC2s and identify the IL-33 receptor on ILC2s as an essential cell-intrinsic regulator of IL-5 production. Further, conditional deletion of Il5 in ILC2s results in defective B1 cell development and immunoglobulin production. Consequently, B1 cells with phosphatidylcholine specific B cell receptor rearrangements are diminished in ILC2-deficient mice. Thus, our data establish an essential function of ILC2s in supporting B1 cells and antibody production at barrier surfaces.

Unraveling the causal associations between systemic cytokines and six inflammatory skin diseases

BackgroundPrevious observational studies have reported that systemic cytokines are associated with the risk of inflammatory skin diseases, but their conclusions remain controversial. MethodWe conducted a two-sample Mendelian randomization analysis to assess the relationship between systemic cytokines and six inflammatory skin disorders (including alopecia areata (AA), acne, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis (PS) and vitiligo), based on datasets from EArly Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium, acne GWAS conducted by Maris Teder Laving et al., IEU Open GWAS, and FinnGen database. Inverse-variance weighted (IVW) method was conducted in primary MR analysis, and supplemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO. ResultsBy integrating the findings from both primary and sensitivity analyses, we identified ten systemic cytokines linked to the risk of six skin diseases using the IVW method. Briefly, four cytokines increased the risk of corresponding skin diseases: β-nerve growth factor (β-NGF) to AA (p = 0.005) and HS (p = 0.001), interleukin-8 (p = 0.014) to acne; interleukin-5 (p = 0.042) to AD; interleukin-13 (p = 0.049) to PS. In the meantime, seven cytokines could have protective effect on specific skin diseases: interleukin-9 (p = 0.040) and interleukin-2 receptor subunit alpha (IL-2ra) (p = 0.020) on AA; macrophage inflammatory protein (MIP)-1β (p = 0.020) on acne; monokine induced by IFN-γ (p = 0.006) on AD; interleukin-16 (p = 0.038), MIP-1β (p = 0.017) and IL-2ra (p = 0.020) on PS. ConclusionsThis study reveals 13 causal associations between systemic cytokines and 6 skin diseases, offering new perspectives on the prevention and management of widespread inflammatory skin disorders.

Real-World Evaluation of Dupilumab in the Long-Term Management of Eosinophilic Chronic Rhinosinusitis with Nasal Polyps: A Focus on IL-4 and IL-13 Receptor Blockade

Background and Objectives: Chronic rhinosinusitis (CRS) is a complex inflammatory condition of the nasal passages that severely impairs quality of life. Type 2 CRS is characterized by eosinophilic inflammation, driven by cytokines like IL-4, IL-5, and IL-13. These cytokines are key to CRS pathogenesis and contribute to a heavy disease burden, especially with comorbidities. This study assessed dupilumab, a monoclonal antibody targeting IL-4 and IL-13 signaling, to evaluate its efficacy in reducing the disease burden in patients with CRS with nasal polyps (CRSwNP). Materials and Methods: The patients received subcutaneous dupilumab for 42 weeks. The outcomes included Nasal Polyp Score (NPS); Sino-Nasal Outcome Test (SNOT-22), Numeric Rating Scale (NRS), and Visual Analog Scale (VAS) scores; total IgE; and olfactory function. Results: Significant improvements were observed across the NPS and SNOT-22, NRS, and VAS scores after 42 weeks. Their total IgE levels were reduced, though a transient increase in peripheral eosinophilia appeared at 16 weeks. The patients also reported substantial improvements in olfactory function and high satisfaction with the treatment, supporting dupilumab’s potential in reducing both symptom severity and inflammation in CRSwNP. Conclusions: These results indicate that dupilumab may be an effective treatment for CRSwNP, offering significant symptom relief, improved olfactory function, and enhanced quality of life. High satisfaction levels suggest that dupilumab may provide therapeutic advantages over the conventional CRS treatments, though further studies are warranted to confirm its long-term benefits.

Interleukin 15-Presenting Nanovesicles with Doxorubicin-Loaded Ferritin Cores for Cancer Immunochemotherapy.

Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non-specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin-loaded ferritin (Dox-Fn) are reported. The DoxFILN significantly enhances the densities and activities of intratumoral CTLs and NK cells. Mechanistically, DoxFILN undergoes deshelling in the acidic tumor microenvironment, releasing Dox-Fn and membrane-bound IL15c. Dox-Fn selectively target transferrin receptors on cancerous cells, facilitating intracellular Dox release and inducing immunogenic cell death. Concurrently, membrane-bound IL15c recognizes and activates IL15 receptor β/γc heterodimers, leading to a remarkable increase in the proliferation and activation of CTLs (16-fold and 28-fold) and NK cells (37-fold and 50-fold). The IL15-displaying nanovesicle introduced here holds promise as a potential platform for immunochemotherapy in the treatment of cancer.

Transcriptomic Profiling Reveals Altered Expression of Genes Involved in Metabolic and Immune Processes in NDV-Infected Chicken Embryos

Objective: The poultry industry is significantly impacted by viral infections, particularly Newcastle Disease Virus (NDV), which leads to substantial economic losses. It is essential to comprehend how the sequence of development affects biological pathways and how early exposure to infections might affect immune responses. Methods: This study employed transcriptome analysis to investigate host–pathogen interactions by analyzing gene expression changes in NDV-infected chicken embryos’ lungs. Result: RNA-Seq reads were aligned with the chicken reference genome (Galgal7), revealing 594 differentially expressed genes: 264 upregulated and 330 downregulated. The most overexpressed genes, with logFC between 8.15 and 8.75, included C8A, FGG, PIT54, FETUB, APOC3, and FGA. Notably, downregulated genes included BPIFB3 (−4.46 logFC) and TRIM39.1 (−4.26 logFC). The analysis also identified 29 novel transcripts and 20 lncRNAs that were upregulated. Gene Ontology and KEGG pathways’ analyses revealed significant alterations in gene expression related to immune function, metabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. Key metabolic genes, such as ALDOB (3.27 logFC), PRPS2 (2.66 logFC), and XDH (2.15 logFC), exhibited altered expression patterns, while DCK2 (−1.99 logFC) and TK1 (−2.11 logFC) were also affected. Several immune-related genes showed significant upregulation in infected lung samples, including ALB (6.15 logFC), TLR4 (1.86 logFC), TLR2 (2.79 logFC), and interleukin receptors, such as IL1R2 (3.15 logFC) and IL22RA2 (1.37 logFC). Conversely, genes such as CXCR4 (−1.49 logFC), CXCL14 (−2.57 logFC), GATA3 (−1.51 logFC), and IL17REL (−2.93 logFC) were downregulated. The higher expression of HSP genes underscores their vital role in immune responses. Conclusion: Comprehension of these genes’ interactions is essential for regulating viral replication and immune responses during infections, potentially aiding in the identification of candidate genes for poultry breed improvement amidst NDV challenges.

Proteomic Alterations in Retinal Müller Glial Cells Lacking Interleukin-6 Receptor: A Comprehensive Analysis.

Interleukin-6 (IL-6) is an inflammatory cytokine implicated in various retinal pathologies and functions primarily through two signaling pathways: cis-signaling via IL-6 binding to its membrane-bound receptor (IL-6Rα), and trans-signaling via IL-6 binding to soluble IL-6 receptor (sIL-6R). Because the differential effects of IL-6 signaling in retinal Müller glial cells (MGCs) remain unclear, we generated an MGC-specific Il6ra-/- knockout (KO) mouse to eliminate IL-6Rα and, consequently, IL-6 cis-signaling in MGCs. In this study, we examined the proteomic changes in MGCs isolated from KO mice lacking a functional IL-6Rα. The proteomes of MGCs isolated from wild-type (WT) and KO mice were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and validated by parallel reaction monitoring (PRM). Relevant biological functions and pathways were examined using Gene Ontology and Ingenuity Pathway Analysis. LC-MS/MS detected 1866 proteins, of which 81 were significantly altered (41 upregulated, 40 downregulated). PRM analysis confirmed differential expression of Ptgis (fold change [FC] = 3.63), Dpep1 (FC = 2.79), Fmo1 (FC = 2.77), Igfbp7 (FC = 2.07), Rpb1 (FC = 1.73), Pygp (FC = 1.46), Niban 1 (FC = 0.58), Mest (FC = 0.48), and Aldh3a1 (FC = 0.30). The significantly altered proteins are involved in oxidative stress balance, inflammation, mitochondrial dysfunction, and regulation of vascular endothelial growth factor (VEGF) signaling. The absence of IL-6Rα in KO MGCs corresponded to significant changes in their proteomic profile, highlighting the impact of autocrine IL-6 signaling on MGC function. This study provides a basis for future research evaluating distinct roles of IL-6 in MGCs and subsequent effects on retinal pathology.

Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment

BackgroundPancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling...