Interleukin-1 Receptor Research Articles

Biologics in congenital ichthyosis: are they effective?

Congenital ichthyoses (CI) comprise a heterogeneous group of genetic diseases requiring lifelong treatment and having a major effect on quality of life. Conventional treatments reduce scaling and skin discomfort; however, they usually have little or no effect on erythema and pruritus. The identification of cytokine alterations in CI raised the possibility of repurposing available biologics. Several case reports in the literature report successes using different biologics. We aimed to report the effects of biologics in real life. This was a retrospective, observational, international multicenter study of patients with CI treated with at least one biologic for a minimum of 3 months. The effect of the biologics was evaluated using an Investigator Global Assessment-Change (IGA-C) scale. A comprehensive literature search was performed in parallel. A total of 98 patients were included, with a mean age of 19.7 years and both sexes equally represented. Patients with Netherton syndrome (NS) or congenital ichthyosiform erythroderma (CIE) represented the majority of patients (30% and 21.4%, respectively). Most patients (84.7%) had a severe or very severe form of CI. The most frequently used biologics were inhibitors targeting interleukin-17 (IL-17), IL-12/IL-23, or the IL-4 receptor. The mean duration of treatment was 22+20.1 months. There were 45 responders (45.9%), including 18 patients (18.3%) who were good responders; all had an erythrodermic CI subset and received one of the three main biologics. In 2 NS and CIE, IL-12/IL-23 and IL-4 receptor inhibitors tended to be most effective. Review of the literature revealed a shorter mean duration of use of biologics (11.5+8.5 months) and higher percentage of responders (85.7%), suggesting reporter bias. This series identified subsets of CI that may respond to biologics and will aid in designing future clinical trials of biologics for CI.

Noncontact 3D Bioprinting of Proteinaceous Microarrays for Highly Sensitive Immunofluorescence Detection within Clinical Samples.

Immunofluorescence assays are extensively used for the detection of disease-associated biomarkers within patient samples for direct diagnosis. Unfortunately, these 2D microarrays suffer from low repeatability and fail to attain the low limits of detection (LODs) required to accurately discern disease progression for clinical monitoring. While three-dimensional microarrays with increased biorecognition molecule density stand to circumvent these limitations, their viscous component materials are not compatible with current microarray fabrication protocols. Herein, we introduce a platform for 3D microarray bioprinting, wherein a two-step printing approach enables the high-throughput fabrication of immunosorbent hydrogels. The hydrogels are composed entirely of cross-linked proteins decorated with clinically relevant capture antibodies. Compared to two-dimensional microarrays, these proteinaceous microarrays offer 3-fold increases in signal intensity. When tested with clinically relevant biomarkers, ultrasensitive single-plex and multiplex detection of interleukin-6 (LOD 0.3 pg/mL) and tumor necrosis factor receptor 1 (LOD 1 pg/mL) is observed. When challenged with clinical samples, these hydrogel microarrays consistently discern elevated levels of interleukin-6 in blood plasma derived from patients with systemic blood infections. Given their easy-to-implement, high-throughput fabrication, and ultrasensitive detection, these three-dimensional microarrays will enable better clinical monitoring of disease progression, yielding improved patient outcomes.

The role of IL15 in angiotensin II-mediated cardiac remodelling

Abstract Hypertension (HTN) mediated target organ damage, such as cardiac remodelling, is a major cause of death and disability. Cytokines are important regulators of cardiac function, inflammation, and remodelling in cardiovascular disease. Increased levels of interleukin 15 (IL15) have been noted in HTN, but its role in HTN heart disease remains unknown. This study investigates the role of the IL15 axis in the pathogenesis of cardiac remodelling in HTN. Male 12-week-old IL15 receptor α knock-out (IL15RAKO), IL15 knock-out (IL15KO) and matching wild type (WT) mice were administered vehicle or angiotensin II (AngII) (490 ng/min/kg) for 2 weeks by osmotic minipump. Blood pressure was measured by tail cuff (n=5-8). Cardiac function was analysed by echocardiography (n=3-4). Cardiac infiltrating immune cells were analysed by flow cytometry (n=2-3 for IL15RAKO, n=6-10 for IL15KO). Cardiac remodelling was assessed by picrosirius red, WGA staining (n=5-8) and expression of markers of remodelling using RT-qPCR and western blots (n=5-8). Data are presented as mean±SEM and analysed using two-way ANOVA. AngII infusion caused a significant increase in systolic blood pressure in WT and IL15KO animals. In contrast, in IL15RAKO, the response to AngII was blunted. This was in line with a decrease in ejection fraction, however only WT mice had an increase in global longitudinal strain (-20.3±2.0 vs -10.9±1.2, p=0.0039 in WT and 19.9±0.8 vs -16.0±2.1, p=0.1878 in IL15RAKO). HTN was associated with increased cardiac IL15 protein levels in mice. The heart-to-body ratio, along with cardiomyocyte cross-sectional, were significantly increased in WT, but not in IL15RAKO HTN mice. Furthermore, histological analysis showed significantly higher cardiac collagen accumulation in WT but not IL15RAKO upon AngII infusion (5.8±1.0% in WTvvs. 2.1±0.5% in IL15RAKO, p=0.0021). This was in line with a higher expression of col1a1 in WT but not IL15RAKO HTN hearts (20.0±6.0 vs 4.5±1.7, p=0.0173). Similarly, the FN1 protein level was significantly increased in WT but not IL15RAKO AngII-treated mice. These changes were associated with a higher number of Cd11b+ macrophages accumulated in WT hypertensive hearts only. In contrast to IL15RAKO, mice lacking IL15 showed similar increases in global longitudinal strain, heart hypertrophy, and cardiomyocyte cross-sectional area as WT mice upon AngII infusion. Similarly, IL15KO hypertensive hearts showed a significant increase of col1a1 and FN1 in comparison to vehicle-treated mice. A similar level of Cd11b+ macrophages was found in hypertensive IL15KO and WT mice's hearts. In conclusion, IL15RA, but not IL15, plays a critical role in cardiac remodelling mediated by AngII infusion. This suggests that the IL15-IL15RA axis may play an important yet complex role in hypertensive heart disease.

A Novel Subset of Regulatory T Cells Induced by B Cells Alleviate the Severity of Immunological Diseases.

Regulatory T (Treg) cells are crucial for maintaining immune tolerance by suppressing response to self-antigens and harmless antigens to prevent autoimmune diseases and uncontrolled immune responses. Therefore, using Treg cells is considered a therapeutic strategy treating inflammatory diseases. Based on their origin, Treg cells are classified into thymus-derived, peripherally induced, and in vitro induced Treg cells. Our group discovered a novel Treg cell subset, namely, Treg-of-B (Treg/B) cells, generated by culturing CD4+CD25- T cells with B cells, including Peyer's patch B cells, splenic B cells and peritoneal B1a cells, for 3days. Treg/B cells express CD44, OX40 (CD134), cytotoxic T-lymphocyte-associated antigen-4 (CD152), glucocorticoid-induced tumor necrosis factor receptor family-related protein (CD357), interleukin-10 receptor, lymphocyte activation gene-3 (CD223), inducible co-stimulator (CD278), programmed-death 1 (CD279), tumor necrosis factor receptor II, and high levels of IL-10, but not forkhead box protein P3, similar to type 1 Treg (Tr1) cells. However, unlike Tr1 cells, Treg/B cells do not express CD103, CD226, and latency-associated peptide. Treg/B cells have been applied for the treatment of some murine models of inflammatory diseases, including allergic asthma, inflammatory bowel disease, collagen-induced arthritis, gout, psoriasis and primary biliary cholangitis. This review summarizes the current knowledge of Treg/B cells.

Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection.

Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.

Real-life experience with rilonacept for the treatment of recurrent pericarditis

Abstract Background Rilonacept, a soluble Interleukin-1 (IL-1) receptor fusion protein that neutralizes IL-1α and IL-1β, has shown efficacy in symptom resolution, weaning of standard-of-care therapies, and reducing the frequency of recurrent pericarditis (RP) episodes in clinical trials. Purpose We aimed to review the efficacy, safety, and duration of treatment with Rilonacept reliance in managing RP in our practice. Methods We analyzed 22 patients with RP treated with Rilonacept, 55 [43-69] years, 11 (50%) females. We reviewed clinical characteristics and outcomes, including the time since initial diagnosis of pericarditis, the presence of pericardial effusion/thickening, the duration of Rilonacept treatment, the ability to wean off steroids, and the recurrence of pericarditis symptoms attempting discontinuation. Results The length of time from the initial diagnosis of pericarditis to Rilonacept initiation was 9 [4-32] months. Fifteen patients out of 22 (68%) had pericardial effusion, 3 (20%) with tamponade requiring pericardiocentesis. Median length of treatment with Rilonacept was 14 [6-23] months, with 17/22 (77%) of patients being treated for ≥ 6 months. All patients who were on steroids (14/22, 64%) were able to discontinue their usage 1 [1-9] months after starting Rilonacept. Of the seventeen who were treated for 6 months or more, 12 (70%) remained on Rilonacept 160 mg weekly at the most recent assessment, 3 (18%) continued treatment with Rilonacept 160 mg every 2 or 4 weeks, and 2 (12%) discontinued Rilonacept treatment after 6 and 50 months. Of the 12 patients who remained on weekly treatment after a period of 6 months, 8 (67%) required Rilonacept for symptom control, 1 (8%) had recurrent symptoms after treatment every 2 weeks, and the remaining 3 (25%) preferred to continue despite a lack of symptoms (Figure 1). Conclusions The efficacy of Rilonacept in treating patients with RP and the ability to stop steroid therapy in the real world is in line with the efficacy data from clinical trials.Figure 1

Plasma protein profile associated with a family history of early-onset coronary heart disease

Abstract Introduction Although family history of coronary heart disease (CHD) is an established risk factor for subsequent CHD, its relation to the circulating proteome is unknown. Proteins linked to coronary atherosclerosis in subjects with a family history could uncover new pathophysiological mechanisms of heritable CHD. Purpose Firstly, we aimed to study the protein profile associated with a family history of early-onset CHD. Secondly, we aimed to identify proteins among which family history was an effect modifier for the association between each protein and coronary atherosclerosis. Methods Plasma levels of proteins were assessed with Olink panels CVD-II and -III in the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort. The coronary segment involvement score (SIS) was assessed from computed tomography angiography. Subjects without known CHD were cross-referenced with national registers to identify records of myocardial infarction or coronary revascularization in any parent before 55 or 65 years of age in males and females, respectively. The associations between a family history of CHD and each protein were studied with linear regression adjusted for age, sex and study site, using a False Discovery Rate (FDR) of 5%. Associations were subsequently adjusted for cardiovascular risk factors. Similarly, associations between each protein and SIS were modelled linearly with an FDR of 5%. For significant proteins, the statistical interactions between each protein and family history for the association between proteins and SIS were studied. Results Of 4,251 subjects, 9.5% had a family history CHD. 43 proteins were significantly associated with family history, and when adjusted for risk factors 29 protein associations remained significant (p<0,05) [Figure 1]. The strongest associations were observed for cathepsin D, paraoxonase 3, interleukin-1 receptor antagonist protein and renin. 79 proteins were associated with SIS at FDR<5%, and family history was a significant effect modifier 18 for proteins [Figure 2]. The strongest modifying effects were observed for transferrin receptor protein 1 (β 0.64, 95% CI 0.25–1.04 for those with family history vs β -0.04, 95% CI -0.14–0.06 in those without, p for interaction=0.001), LDL-receptor (β 0.68, 95% CI 0.36–1.00 vs β 0.18, 95% CI 0.08–0.26) and tissue-type plasminogen activator (β 0.45, 95% CI 0.19–0.70 vs β 0.13, 95% CI 0.05–0.21). Conclusion We found that 43 proteins, with biological features of inflammation and vascular function, were associated with a family history of early-onset CHD. Most were also linked to the coronary atherosclerosis burden. Notably, 18 biomarkers, among them transferrin receptor protein 1, LDL-receptor and tissue-type plasminogen activator, exhibited strong statistical interactions with family history in the association with SIS, indicating that they are of particular importance for the genetic susceptibility and the pathophysiology of heritable CHD.

Macrophage-mediated interleukin-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation

Abstract Background Postoperative atrial fibrillation (poAF) is self-limited AF that occurs within days after cardiac surgery in one-third of patients. Clinical and preclinical studies have demonstrated that the magnitude of the perioperative increase in systemic inflammation, in particular mediated by interleukin (IL)-6, correlates with poAF risk. However, no studies to-date have mechanistically linked IL-6 signaling to fundamental arrhythmia mechanisms or identified the specific cell types driving postoperative atrial IL-6 signaling. Methods We performed single-cell RNA sequencing (scRNAseq), followed by pseudotime trajectory and cell-cell communication analyses on atrial non-myocytes comparing mice with and without poAF. We followed up our scRNAseq findings with pharmacologic and genetic approaches in mice to validate pathways related to macrophage-mediated IL-6 signaling. We used confocal imaging to assess calcium-signaling mechanisms at the single atrial cardiomyocyte (ACM) level and performed parallel patch-clamp studies in isolated human ACMs as well as biochemical analyses of human atrial tissue to assess the translational relevance of our findings. Results Our scRNAseq results demonstrated macrophages to be the most prominently altered cell type in the atria of mice with poAF. Pseudotime trajectory analyses revealed IL-6 to be one of the top inflammatory pathways implicated in macrophage transcriptional state. Indeed, both macrophage depletion and conditional knockout of IL-6 receptors in macrophages were sufficient to prevent poAF. We found that inhibition of STAT3, which is downstream of the IL-6Ra, with FDA-approved phospho-STAT3 inhibitor TTI-101 prevented poAF in mice. Lastly, we demonstrate that enhanced STAT3 activity in poAF promotes arrhythmogenic Ca2+ sparks and waves through ryanodine receptor-2 dysfunction, and that CaMKII inhibition is sufficient to ameliorate Ca2+ mishandling at the single atrial myocyte level. Conclusions Taken together, we use an integrated approach incorporating mouse and human biochemical, functional, and single-cell sequencing data to demonstrate that infiltrating atrial macrophages are fundamentally required for poAF. IL-6 was found to be a critical pathway upregulated in poAF leading to downstream ryanodine receptor-2 dysfunction and atrial arrhythmogenesis. Our findings portend significant therapeutic utility by providing robust mechanistic evidence that targeting the IL-6 axis may be used for poAF prevention and treatment in a clinically amenable timeframe.

The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis.

Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor α subunit (IL-11Rα) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11Rα are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.

The Impact of Acute Ammonia Nitrogen Stress on Serum Biochemical Indicators and Spleen Gene Expression in Juvenile Yellowfin Tuna (Thunnus albacares)

The presence of ammonia nitrogen in water has a significant impact on the serum and spleen of fish, potentially leading to changes in substances such as proteins in the serum while also causing damage to the immune function of the spleen. To investigate the effects of ammonia nitrogen (NH3-N) stress on juvenile yellowfin tuna (Thunnus albacares), this study established three NH3-N concentrations, 0, 5, and 10 mg/L, denoted as L0, L1, and L2, respectively. Serum and spleen samples were collected at 6, 24, and 36 h. The effects of different NH3-N concentrations and exposure times on the physiological status of juvenile fish were investigated by analyzing serum biochemical indices and splenic gene expression. The results indicate that in the L1 group, the serum high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), complement 3 (C3) and complement 4 (C4) levels, and acid phosphatase (ACP) activity showed a trend of initially increasing and then decreasing. In the L2 group, the serum low-density lipoprotein cholesterol (LDL-C), HDL-C, and C4 levels and ACP activity also displayed an initially rising and then declining trend, while TG, C3, and creatinine (CRE) levels and alkaline phosphatase (AKP) activity showed an upward trend. In the L1 group, glutathione peroxidase 1b (GPX1b), interleukin 10 (IL-10), interleukin 6 receptor (IL-6r), and tumor necrosis factor alpha (TNF-α) gene expression levels in the spleen exhibited a trend of first increasing and then decreasing. In the L2 group, IL-10, IL-6r, tumor necrosis factor beta (TNF-β), caspase 2 (casp2), and caspase 9 (casp9) gene expression levels in the spleen also showed an initial increase followed by a decrease. When NH3-N levels are below 5 mg/L, it is recommended to limit stress exposure to no more than 36 h for the juvenile fish. For concentrations ranging from 5 to 10 mg/L, stress should be strictly controlled to within 24 h. Exposure to high NH3-N levels may affect biochemical indicators such as serum lipid metabolism, immunity, and metabolism in juvenile fish, and may damage the expression of antioxidant, immune gene, and apoptosis factors in the spleen. This study aims to deepen our understanding of the effects of NH3-N on juvenile tuna, with the goal of establishing effective water quality monitoring and management strategies. This will ensure the quality of aquaculture water, reduce the harm caused by NH3-N to juvenile yellowfin tuna, and enhance aquaculture efficiency and product quality.

IL-1 receptor antagonist: etiological and drug delivery systems overview.

This article is aims to provide an overview of studies reported in the literature to investigate the etiological role of IL-1/IL-1ra in various disease conditions and the different drug delivery systems developed to achieve IL-1ra as a possible therapeutic option. Studies reported in PubMed, Google scholar, and other open-source literature related to etiological involvement of IL-1ra in pathophysiological conditions and various drug delivery schemes developed for IL-1ra for its efficacy evaluation as a possible treatment for different disease conditions were surveyed. The pathophysiological conditions involving IL-1/IL-1 ra spanned CNS-related disorders, Diabetes, Cardiac disorders, Ocular disease conditions, Gastrointestinal conditions, Tumor growth & metastasis, and miscellaneous conditions. The drug delivery systems developed for IL-1ra included a commercial drug product, Gene therapy, Antibody fusions, Extended-release delivery systems, and Pegylated-IL-1ra systems.

Long-term efficacy and safety of stapokibart for moderate-to-severe atopic dermatitis: 52-week results from a phase 3 trial.

Management of moderate-to-severe atopic dermatitis (AD) needs long-term therapy. Stapokibart is a humanized monoclonal antibody targeting interleukin-4 receptor α subunit (IL-4Rα), a shared receptor for IL-4 and IL-13 which are key pathogenic drivers of AD. In a pivotal phase 3 trial (NCT05265923), significant higher proportions of adult AD patients receiving stapokibart than placebo achieved ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75; 66.9% vs. 25.8%) and Investigator's Global Assessment (IGA) score of 0/1 with ≥2-point reduction (44.2% vs. 16.1%) at Week 16. Herein, we report long-term (52 weeks) efficacy and safety of stapokibart from this trial. After 16-week double-blind treatment completed, patients in both stapokibart and placebo groups entered a 36-week maintenance treatment period and received stapokibart 300 mg every 2 weeks. Concomitant use of topical medications for AD was permitted throughout the maintenance period. Of 476 patients entering maintenance period, 430 completed the treatment. At Week 52, EASI-75 was achieved in 92.5% of patients continuing stapokibart and 88.7% of those switching from placebo to stapokibart, respectively; an IGA score of 0 or 1 with a ≥2-point reduction was achieved in 67.3% and 64.2% of patients, respectively; a ≥4-point reduction in weekly average of daily Peak Pruritus Numerical Rating Scale (PP-NRS) was achieved in 67.3% and 60.5% of patients, respectively. Over the 52-week treatment period, 88.1% of patients reported treatment-emergent adverse events, most were mild or moderate. Long-term treatment with stapokibart demonstrated a sustained efficacy and favorable safety profile in adults with moderate-to-severe AD.

The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control.

Non-linear relationship between soluble interleukin-2 receptor and prognosis of diffuse large B-cell lymphoma.

Despite an emphasis on the prognostic impact of serum soluble interleukin-2 receptor (sIL-2R) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL), whether the prognostic impact of elevated sIL-2R is linear remains unclear. To verify the presence of a non-linear association between sIL-2R level at diagnosis and overall survival (OS) in patients with newly diagnosed DLBCL, we conducted a multi-center, observational retrospective study. Among 488 analyzable patients, Cox proportional hazards modeling identified serum sIL-2R level at diagnosis as an independent predictor of OS. Multivariate Cox hazard modeling with restricted cubic spline model demonstrated that the relationship between serum sIL-2R level and OS was clearly non-linear (P for effect of sIL-2R = 0.002; P for non-linearity = 0.015). Mortality risk increased gradually as sIL-2R levels increased and plateaued at approximately 5,000 U/mL. Segmented regression analysis revealed that the trend in negative prognostic impact from a gradual increase in serum sIL-2R level changed significantly, with a breakpoint at approximately 2,000 U/mL. Multivariate receiver operating characteristic curves showed a significant improvement in prediction ability when serum sIL-2R level was added to the International Prognostic Index (IPI). Serum sIL-2R level at diagnosis was not only a prognostic factor, but also improved predictive accuracy for OS when incorporated with the IPI. However, the negative correlation between increasing sIL-2R and prognosis was non-linear.

Some parameters of the immune system in women with hyperandrogenism

The article is dedicated to studying certain parameters of the immune system, which holds great significance in obstetrics and gynecology. Examining immune system parameters allows for identifying disruptions in reproductive-aged women with hyperandrogenism, which holds crucial practical implications. The authors conducted an immunological study of women with hyperandrogenism and women without this pathology. The aim of the study was to investigate the immune system status in women suffering from hyperandrogenism. Materials and methods of the study: 58 reproductive-aged women diagnosed with hyperandrogenism, under observation at the Women’s Health Center “AyolCare” in Tashkent, were examined. Comprehensive clinical and laboratory examinations were conducted for all women. The control group comprised 35 practically healthy reproductive-aged women. The obtained results indicate that women with altered hormonal balance, including those with hyperandrogenism, experience specific changes in the immune system. The conducted research revealed that the levels of T lymphocytes and T helper/inducer cells decrease, while the number of T killer cells, CD25+ cells (carrying IL-2 receptor), and CD95+ cells (carrying apoptosis signaling receptor) increases. The elevated levels of CD95+ cells indicate increased activation of apoptosis processes, which serve as a protective function of T killer cells. This increase in lymphocyte activation is likely associated with elevated levels of mature activated macrophages and a range of cytokines they produce, which directly stimulate lymphocytes. The detected imbalance in immunological parameters likely indicates that in hyperandrogenism, either the elimination of activated clones of T helper cells is absent or disrupted, which usually leads to the formation of immune response suppression. The increase in the number of activated clones of T lymphocytes is observed in the decreased process of their apoptosis, which is likely intensified by the influence of androgens.

IL-27 attenuated macrophage injury and inflammation induced by Mycobacterium tuberculosis by activating autophagy.

Interleukin-27 (IL-27) is a cytokine that is reported to be highly expressed in the peripheral blood of patients with pulmonary tuberculosis (PTB). IL-27-mediated signaling pathways, which exhibit anti- Mycobacterium tuberculosis (Mtb) properties, have also been demonstrated in macrophages infected with Mtb. However, the exact mechanism remains unclear. This study aimed to clarify the potential molecular mechanisms through which IL-27 enhances macrophage resistance to Mtb infection.Both normal and PTB patients provided bronchoalveolar lavage fluid (BALF). Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and stimulated with 50ng/mL macrophage-colony stimulating factor (M-CSF) to obtain monocyte-derived macrophages (MDMs). Using 100ng/mL phorbol 12-myristate 13-acetate (PMA), THP-1 cells were induced to differentiate into THP-1-derived macrophage-like cells (TDMs). Both MDMs and TDMs were subsequently infected with the Mtb strain H37Rv and treated with 50ng/mL IL-27 prior to infection. The damage and inflammation of macrophages were examined using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and Western blotting.Patients with PTB had elevated levels of IL-27 in their BALF. Preconditioning with IL-27 was shown to reduce H37Rv-induced MDMs and TDMs apoptosis while also decreasing the levels of Cleaved Caspase-3, Bax and the proinflammatory cytokines TNF-α, IL-1β, and IL-6, promoting the expression of Bcl-2 and the anti-inflammatory factors IL-10 and IL-4. Silencing of the IL-27 receptor IL-27Ra increased macrophage damage and inflammation triggered by H37Rv. Mechanistically, IL-27 activates autophagy by inhibiting TLR4/NF-κB signaling and activating the PI3K/AKT signaling pathway, thereby inhibiting H37Rv-induced macrophage apoptosis and the inflammatory response.Our study suggests that IL-27 alleviates H37Rv-induced macrophage injury and the inflammatory response by activating autophagy and that IL-27 may be a new target for the treatment of PTB.

Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection.

Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release. Toxoplasma gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-γ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1-positive cells drives IL-18 release, which potentiates CD4+ T cell IFN-γ production and parasite control. Notably, our Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored CD4+ T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii.

Targeting immune-fibroblast cell communication in heart failure.

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2(CCR2) macrophages and fibroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2+ monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

IL-1 Blockade Mitigates Autism and Cerebral Palsy Traits in Offspring In-Utero Exposed to Group B Streptococcus Chorioamnionitis

Group B Streptococcus (GBS) is one of the most common bacteria responsible for placental and neonatal infection and inflammation resulting in lifelong neurobehavioral impairments. In particular, GBS-induced chorioamnionitis is known in preclinical models to upregulate inflammatory pathways, primarily through the activation of the interleukin-1 (IL-1) pathway, leading to brain injury and subsequent neurodevelopmental issues. Previous studies from our laboratory using Lewis rat pups have shown that male offspring exposed in utero to GBS chorioamnionitis develop brain injuries leading to neurobehavioral impairments such as autistic traits. In the present study, we aimed to explore whether blocking the IL-1 pathway could prevent or mitigate these neurodevelopmental impairments in adulthood. Using our established preclinical model, we administered IL-1 receptor antagonist (IL-1Ra) to dams with GBS-induced chorioamnionitis. Here, we show that IL-1Ra administration to dams reversed autistic and cerebral palsy traits in male adult offspring exposed in utero to GBS. Hence, IL-1 blockade could serve as a therapeutic intervention against pathogen-induced neurodevelopmental disorders. This research supports the need for future human randomized controlled trials to assess IL-1 blockade administered during pregnancy or in newborns as a strategy to reduce the long-term neurobehavioral consequences of prenatal infections, such as autism, cerebral palsy, learning disabilities, and other neurodevelopmental disorders.

Causal relationship between circulating inflammatory proteins and risk of different types of encephalitis: A two-sample Mendelian randomization study

BackgroundCytokines are potent molecules of the immune response. They act at the site of inflammation and circulate in the bloodstream. However, there are few studies on encephalitis and circulating inflammatory proteins. MethodsIn this study, Mendelian randomization (MR) was used to explore the potential causal effect of 91 circulating inflammatory proteins on 3 different types of encephalitis. Causal effects were examined using Steiger, MR-Egger, weighted median, and inverse variance weighting (IVW) methods. IVW methods were primarily used for results interpretation. In addition, sensitivity analyses were performed, including assessment of heterogeneity, horizontal pleiotropy, and Leave-one-out techniques. ResultsWe subjected 91 circulating inflammatory proteins to MR analysis of causality with each of the three types of encephalitis. The results suggested that the inflammatory factors with a potential causal relationship with viral encephalitis were caspase 8, C-X-C motif chemokine 6, interleukin-10, interleukin-15 receptor subunit alpha, interleukin-7, and TNF-beta. Inflammatory factors potentially causally associated with acute disseminated encephalomyelitis are beta-nerve growth factor, cystatin D, interleukin-7,Latency-associated peptide transforming growth factor beta 1,and neurotrophin-3.Inflammatory factors potentially causally associated with autoimmune encephalitis are C–C motif chemokine 25, hepatocyte growth factor, latency-associated peptide transforming growth factor beta 1, programmed cell death 1 ligand 1, sulfotransferase 1A1, and tumor necrosis factor. ConclusionThis finding identifies potential causal effects of certain circulating inflammatory factors on susceptibility to three types of encephalitis. It also suggests the therapeutic potential of modulating the levels of these cytokines. A basis for further research is provided.