BaP/BPDE exposure causes human trophoblast cell dysfunctions and induces miscarriage by up-regulating lnc-HZ06-regulated IL1B.

Exposure to environmental BaP or its metabolite BPDE causes trophoblast cell dysfunctions to induce miscarriage (abnormal early embryo loss), which might be generally regulated by lncRNAs. IL1B, a critical inflammatory cytokine, is closely associated with adverse pregnancy outcomes. However, whether IL1B might cause dysfunctions of BaP/BPDE-exposed trophoblast cells to induce miscarriage, as well as its specific epigenetic regulatory mechanisms, is completely unexplored. In this study, we find that BPDE-DNA adducts, trophoblast cell dysfunctions, and miscarriage are closely associated. Moreover, we also identify a novel lnc-HZ06 and IL1B, both of which are highly expressed in BPDE-exposed trophoblast cells, in villous tissues of recurrent miscarriage patients, and in placental tissues of BaP-exposed mice with miscarriage. Both lnc-HZ06 and IL1B suppress trophoblast cell migration/invasion and increase apoptosis. In mechanism, lnc-HZ06 promotes STAT4-mediated IL1B mRNA transcription, enhances IL1B mRNA stability by promoting the formation of METTL3/HuR/IL1B mRNA ternary complex, and finally up-regulates IL1B expression levels. BPDE exposure promotes TBP-mediated lnc-HZ06 transcription, and thus up-regulates IL1B levels. Knockdown of either murine lnc-hz06 (which down-regulates Il1b levels) or murine Il1b could alleviate miscarriage in BaP-exposed mice. Collectively, this study not only discovers novel biological mechanisms and pathogenesis of unexplained miscarriage but also provides novel potential targets for treatment against BaP/BPDE-induced miscarriage.

An antibody to IL-1 receptor 7 protects mice from LPS-induced tissue and systemic inflammation.

Introduction: Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. Methods: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. Results: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Discussion: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.

Hypericum perforatum L. attenuates depression by regulating Akkermansia muciniphila, tryptophan metabolism and NFκB-NLRP2-Caspase1-IL1ß pathway.

BACKGROUND: Gut microbiota dysbiosis significantly contributes to progression of depression. Hypericum perforatum L. (HPL) is traditionally used in Europe for treating depression. However, its mechanism remains largely underexplored. PURPOSE: This study aims to investigate the pivotal gut microbiota species and microbial signaling metabolites associated with the antidepressant effects of HPL. METHODS: Fecal microbiota transplantation was used to assess whether HPL mitigates depression through alterations in gut microbiota. Microbiota and metabolic profiling of control, chronic restraint stress (CRS)-induced depression, and HPL-treated CRS mice were examined using 16S rRNA gene sequencing and metabolomics analysis. The influence of gut microbiota on HPL's antidepressant effects was assessed by metabolite and bacterial intervention experiments. RESULTS: HPL significantly alleviated depression symptoms in a manner dependent on gut microbiota and restored gut microbial composition by enriching Akkermansia muciniphila (AKK). Metabolomic analysis indicated that HPL regulated tryptophan metabolism, reducing kynurenine (KYN) levels derived from microbiota and increasing 5-hydroxytryptophan (5-HTP) levels. Notably, supplementation with KYN activated the NFκB-NLRP2-Caspase1-IL1ß pathway and increased proinflammatory IL1ß in the hippocampus of mice with depression. Interestingly, mono-colonization with AKK notably increased 5-hydroxytryptamine (5-HT) and decreased KYN levels, ameliorating depression symptoms through modulation of the NFκB-NLRP2-Caspase1-IL1ß pathway. CONCLUSIONS: The promising therapeutic role of HPL in treating depression is primarily attributed to its regulation of the NFκB-NLRP2-Caspase1-IL1ß pathway, specifically by targeting AKK and tryptophan metabolites.

IL-1ra loaded chondroitin sulfate-functionalized microspheres for minimally invasive treatment of intervertebral disc degeneration.

Presently, the clinical treatment of intervertebral disc degeneration (IVDD) remains challenging, but the strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in the nucleus pulposus (NP) has become an effective way to alleviate IVDD. IL-1ra, a natural antagonist against IL-1ß, can mitigate inflammation and promote regeneration in IVDD. Chondroitin sulfate (CS), an important component of the NP, can promote ECM synthesis and delay IVDD. Thus, these were chosen and integrated into functionalized microspheres to achieve their synergistic effects. First, CS-functionalized microspheres (GelMA-CS) with porous microstructure, good monodispersion, and about 200 µm diameter were efficiently and productively fabricated using microfluidic technology. After lyophilization, the microspheres with good local injection and tissue retention served as the loading platform for IL-1ra and achieved sustained release. In in vitro experiments, the IL-1ra-loaded microspheres exhibited good cytocompatibility and efficacy in inhibiting the inflammatory response of NP cells induced by lipopolysaccharide (LPS) and promoting the secretion of ECM. In in vivo experiments, the microspheres showed good histocompatibility, and local, minimally invasive injection of the IL-1ra-loaded microspheres could reduce inflammation, maintain the height of the intervertebral disc (IVD) and the water content of NP close to about 70 % in the sham group, and retain the integrated IVD structure. In summary, the GelMA-CS microspheres served as an effective loading platform for IL-1ra, eliminated inflammation through the controlled release of IL-1ra, and promoted ECM synthesis via CS to delay IVDD, thereby providing a promising intervention strategy for IVDD. STATEMENT OF SIGNIFICANCE: The strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in nucleus pulposus (NP) has shown great potential prospects for alleviating intervertebral disc degeneration (IVDD). From the perspective of clinical translation, this study developed chondroitin sulfate functionalized microspheres to act as the effective delivery platform of IL-1ra, a natural antagonist of interleukin-1ß. The IL-1ra loading microspheres (GelMA-CS-IL-1ra) showed good biocompatibility, good injection with tissue retention, and synergistic effects of inhibiting the inflammatory response induced by lipopolysaccharide and promoting the secretion of ECM in NPCs. In vivo, they also showed the beneficial effect of reducing the inflammatory response, maintaining the height of the intervertebral disc and the water content of the NP, and preserving the integrity of the intervertebral disc structure after only one injection. All demonstrated that the GelMA-CS-IL-1ra microspheres would have great promise for the minimally invasive treatment of IVDD.

Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1ß Release.

Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1ß, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

ZO-1 and IL-1RAP Phosphorylation: Potential Role in Mediated Brain-Gut Axis Dysregulation in Irritable Bowel Syndrome-like Stressed Mice.

Background and Objectives: Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder often exacerbated by stress, influencing the brain-gut axis (BGA). BGA dysregulation, disrupted intestinal barrier function, altered visceral sensitivity and immune imbalance defects underlying IBS pathogenesis have been emphasized in recent investigations. Phosphoproteomics reveals unique phosphorylation details resulting from environmental stress. Here, we employ phosphoproteomics to explore the molecular mechanisms underlying IBS-like symptoms, mainly focusing on the role of ZO-1 and IL-1RAP phosphorylation. Materials and Methods: Morris water maze (MWM) was used to evaluate memory function for single prolonged stress (SPS). To assess visceral hypersensitivity of IBS-like symptoms, use the Abdominal withdrawal reflex (AWR). Colonic bead expulsion and defecation were used to determine fecal characteristics of the IBS-like symptoms. Then, we applied a phosphoproteomic approach to BGA research to discover the molecular mechanisms underlying the process of visceral hypersensitivity in IBS-like mice following SPS. ZO-1, p-S179-ZO1, IL-1RAP, p-S566-IL-1RAP and GFAP levels in BGA were measured by western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay to validate phosphorylation quantification. Fluorescein isothiocyanate-dextran 4000 and electron-microscopy were performed to observe the structure and function of the intestinal epithelial barrier. Results: The SPS group showed changes in learning and memory ability. SPS exposure affects visceral hypersensitivity, increased fecal water content, and significant diarrheal symptoms. Phosphoproteomic analysis displayed that p-S179-ZO1 and p-S566-IL-1RAP were significantly differentially expressed following SPS. In addition, p-S179-ZO1 was reduced in mice's DRG, colon, small intestine, spinal and hippocampus and intestinal epithelial permeability was increased. GFAP, IL-1ß and p-S566-IL-1RAP were also increased at the same levels in the BGA. And IL-1ß showed no significant difference was observed in serum. Our findings reveal substantial alterations in ZO-1 and IL-1RAP phosphorylation, correlating with increased epithelial permeability and immune imbalance. Conclusions: Overall, decreased p-S179-ZO1 and increased p-S566-IL-1RAP on the BGA result in changes to tight junction structure, compromising the structure and function of the intestinal epithelial barrier and exacerbating immune imbalance in IBS-like stressed mice.

Interleukin-1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma-induced increase in intra-hepatic immune cells.

BACKGROUND AND AIM: Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC. METHODS: Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1ß levels in human and mouse serum were assessed. RESULTS: Interleukin-1ß levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1ß levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1-/-) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1ß concentration. IL-1R1-/- mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver. CONCLUSIONS: Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.

Exploring causal correlations between inflammatory cytokines and intervertebral disc degeneration: A Mendelian randomization.

Background: Inflammatory cytokines have been reported to be related to intervertebral disc degeneration (IVDD) in several previous studies. However, it remains unclear about the causal relationship between inflammatory cytokines and IVDD. This study employs Mendelian randomization (MR) to analyze the causal link between inflammatory cytokines and the risk of IVDD. Method: We used genetic variants associated with inflammatory cytokines from a meta-analysis of genome-wide association study (GWAS) in 8293 Finns as instrumental variables and IVDD data were sourced from the FinnGen consortium. The main analytical approach utilized Inverse-Variance Weighting (IVW) with random effects to assess the causal relationship. Additionally, complementary methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR pleiotropy residual sum and outlier were employed to enhance the robustness of the final results. Result: We found interferon-gamma (IFN-γ, p = 2.14 × 10-6, OR = 0.870, 95% CI = 0.821-0.921), interleukin-1 beta (IL-1b, p = 0.012, OR = 0.951, 95% CI = 0.914-0.989), interleukin-4 (IL-4, p = 0.034, OR = 0.946, 95% CI = 0.899-0.996), interleukin-18 (IL-18, p = 0.028, OR = 0.964, 95% CI = 0.934-0.996), granulocyte colony-stimulating factor (GCSF, p = 0.010, OR = 0.919, 95% CI = 0.861-0.980), and Stromal cell-derived factor 1a (SDF1a, p = 0.014, OR = 1.072, 95% CI = 1.014-1.134) were causally associated with risk of IVDD. Conclusion: Our MR analyses found a potential causal relationship between six inflammation cytokines (IFN-γ, IL-1b, IL-4, IL-18, SDF1a, and GCSF) and altered IVDD risk.

Computer modeling of the peculiarities in the interaction of IL-1 with its receptors in schizophrenia.

One of the primary theories regarding the development of schizophrenia revolves around genetics, indicating the involvement of hereditary factors in various processes, including inflammation. Research has demonstrated that inflammatory reactions occurring in microglia can impact the progression of the disease. It has also been established that genetically determined changes in IL-1 can contribute to schizophrenia, thereby confirming the role of the IL-1 gene cluster in disease susceptibility. The aim of this study is a computer-based assessment of the structural interactions of IL-1 proteins with their receptors in schizophrenia. The study utilized the DisGeNET database, enabling the assessment of the reliability of identified IL-1 polymorphisms. Polymorphisms were also sought using NCBI PubMed. The NCBI Protein service was employed to search for and analyze the position of the identified polymorphisms on the chromosome. Structures for modeling were extracted from the Protein Data Bank database. Protein modeling was conducted using the SWISS-MODEL server, and protein interaction modeling was performed using PRISM. Notably, this study represents the first prediction of the interactions of IL-1α, IL-1ß, and IL- 1RA proteins, taking into account the presence of single-nucleotide polymorphisms associated with schizophrenia in the sequence of the corresponding genes. The results indicate that the presence of SNP rs315952 in the IL-1RA protein gene, associated with schizophrenia, may lead to a weakening of the IL-1RA binding to receptors, potentially triggering the initiation of the IL-1 signaling pathway by disrupting or weakening the IL-1RA binding to receptors and facilitating the binding of IL-1 to them. Such alterations could potentially lead to a change in the immune response. The data obtained contribute theoretically to the development of ideas about the molecular mechanisms through which hereditary factors in schizophrenia influence the interactions of proteins of the IL-1 family, which play an important role in the processes of the immune system.

Correlation between fat-soluble vitamin levels and inflammatory factors in paediatric community-acquired pneumonia: A prospective study.

Community-acquired pneumonia (CAP) is a common respiratory disease in children. This prospective cohort study of 110 children with CAP and 100 healthy children investigated the relationship between the levels of vitamin A, D and E and inflammatory markers, such as tumour necrosis factor (TNF-a), interleukin-1 (IL-1), interleukin-10 (IL-10), neutrophils (NE) and C-reactive protein (CRP), in CAP. The haemoglobin, leukocyte concentration, NE, monocytes and CRP concentration in the CAP group showed significant differences (P < 0.05). The levels of vitamin A, D and E in the CAP group were lower than those in the control group, while the levels of TNF-a and IL-1 were higher than in the control group; the differences were statistically significant (P < 0.05). The IL-10 levels showed no significant differences (P > 0.05). Pearson analysis revealed that the vitamin A, D and E levels were all correlated with the TNF-a, IL-10 and CRP levels (P < 0.05). The vitamin A, D and E levels of the CAP children were lower than those of the healthy children. Thus, the content of fat-soluble vitamins is correlated with the secretion of TNF-a and IL-10. The research provides a new direction for the prevention, diagnosis and treatment of CAP.

Effects of a ß-Glucan-Rich Blend of Medicinal Mushrooms and Botanicals on Innate Immune Cell Activation and Function Are Enhanced by a Very Low Dose of Bovine Colostrum Peptides.

Nutraceutical immune support offers potential for designing blends with complementary mechanisms of action for robust support of innate immune alertness. We documented enhanced immune activation when bovine colostrum peptides (BC-Pep) were added to an immune blend (IB) containing ß-glucans from yeast, shiitake, maitake, and botanical non-ß-glucan polysaccharides. Human peripheral blood mononuclear cells (PBMCs) were cultured with IB, BC-Pep, and IB + BC-Pep for 20 h, whereafter expression of the activation marker CD69 was evaluated on NK cells, NKT cells, and T cells. Cytokine levels were tested in culture supernatants. PBMCs were co-cultured with K562 target cells to evaluate T cell-mediated cytotoxicity. IB + BC-Pep triggered highly significant increases in IL-1ß, IL-6, and TNF-α, above that of cultures treated with matching doses of either IB or BC-Pep. NK cell and T cell activation was increased by IB + BC-Pep, reaching levels of CD69 expression several fold higher than either BC-Pep or IB alone. IB + BC-Pep significantly increased T cell-mediated cytotoxic killing of K562 target cells. This synergistic effect suggests unique amplification of signal transduction of NK cells and T cells due to modulation of IB-induced signaling pathways by BC-Pep and is of interest for further pre-clinical and clinical testing of immune defense activity against virally infected and transformed cells.

Urticarial Vasculitis.

Urticarial vasculitis is a rare autoimmune disorder characterized by persistent edematous papules and plaques on the skin that last longer than 24 hours, often accompanied by systemic symptoms such as joint pain and fever. Unlike common urticaria, this condition involves inflammation of small blood vessels, leading to more severe and long-lasting skin lesions with a tendency to leave a bruiselike appearance. Diagnosis is challenging and may require a skin biopsy. Associated with underlying autoimmune diseases, treatment involves managing symptoms with medications such as antihistamines and corticosteroids, addressing the immune system's dysfunction, and treating any concurrent autoimmune conditions.

Emerging insights into the role of IL-1 inhibitors and colchicine for inflammation control in type 2 diabetes.

Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1ß (IL-1ß) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1ß production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.

Molecular aspects of Interleukin-36 cytokine activation and regulation.

Interleukin-36 (IL-36) cytokines are structurally similar to other Interleukin-1 superfamily members and are essential to convey inflammatory responses at epithelial barriers including the skin, lung, and gut. Due to their potent effects on immune cells, IL-36 cytokine activation is regulated on multiple levels, from expression and activation to receptor binding. Different IL-36 isoforms convey specific responses as a consequence of particular danger- or pathogen-associated molecular patterns. IL-36 expression and activation are regulated by exogenous pathogens, including fungi, viruses and bacteria but also by endogenous factors such as antimicrobial peptides or cytokines. Processing of IL-36 into potent bioactive forms is necessary for host protection but can elevate tissue damage. Indeed, exacerbated IL-36 signalling and hyperactivation are linked to the pathogenesis of diseases such as plaque and pustular psoriasis, emphasising the importance of understanding the molecular aspects regulating IL-36 activation. Here, we summarise facets of the electrochemical properties, regulation of extracellular cleavage by various proteases and receptor signalling of the pro-inflammatory and anti-inflammatory IL-36 family members. Additionally, this intriguing cytokine subfamily displays many characteristics that are unique from prototypical members of the IL-1 family and these key distinctions are outlined here.

Early-life bisphenol A exposure causes neuronal pyroptosis in juvenile and adult male rats through the NF-κB/IL-1ß/NLRP3/caspase-1 signaling pathway: exploration of age and dose as effective covariates using an in vivo and in silico modeling approach.

Bisphenol A (BPA), a common endocrine-disrupting chemical, is found in a wide range of home plastics. Early-life BPA exposure has been linked to neurodevelopmental disorders; however, the link between neuroinflammation, pyroptosis, and the development of psychiatric disorders is rarely studied. The current study attempted to investigate the toxic effect of BPA on inflammatory and microglial activation markers, as well as behavioral responses, in the brains of male rats in a dose- and age-dependent manner. Early BPA exposure began on postnatal day (PND) 18 at dosages of 50 and 125 mg/kg/day. We started with a battery of behavioral activities, including open field, elevated plus- and Y-maze tests, performed on young PND 60 rats and adult PND 95 rats. BPA causes anxiogenic-related behaviors, as well as cognitive and memory deficits. The in vivo and in silico analyses revealed for the first time that BPA is a substantial activator of nuclear factor kappa B (NF-κB), interleukin (IL)-1ß, -2, -12, cyclooxygenase-2, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, with higher beclin-1 and LC3B levels in BPA rats' PFC and hippocampus. Furthermore, BPA increased the co-localization of caspase-1 immunoreactive neurons, as well as unique neurodegenerative histopathological hallmarks. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation are involved with changes in the brain after postnatal BPA exposure and that these alterations may be linked to the development of psychiatric conditions later in life. Collectively, our findings indicate that BPA triggers anxiety-like behaviors and pyroptotic death of nerve cells via the NF-κB/IL-1ß/NLRP3/Caspase-1 pathway.

Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Single-cell analysis of tumor microenvironment and cell adhesion reveals that interleukin-1 beta promotes cancer cell proliferation in breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), which is so called because of the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) receptors on the cancer cells, accounts for 10%-15% of all breast cancers. The heterogeneity of the tumor microenvironment is high. However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood. METHODS: We analyzed single-cell RNA sequencing data from five HER2 positive, 12 ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry. RESULTS: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2-integrin-aLb2 complex, and then release interleukin 1 beta (IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth. CONCLUSION: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.

Schnitzler's Syndrome-Diagnostic Experience, Approaches to Therapy, and Patient Management according to a Multicenter Russian Cohort.

The objectives of the study were to present the experience of diagnosis, management, and therapy with IL-1 inhibitors in patients with Schnitzler's syndrome (SchS) according to a multicenter Russian cohort. An observational retrospective study for a 10-year period (2012-2022) involved 17 patients with SchS who were admitted to the hospital or were observed on an outpatient basis (eight women and nine men). The diagnosis of all of them corresponded to the Strasbourg diagnostic criteria. The age of patients ranged from 25 to 81 years (Me 53[46; 56]). The age at the time of the onset of the disease ranged from 20 to 72 years (Me 46[39; 54]), the duration of the disease before diagnosis ranged from 1 to 35 years (Me 6.5[3; 6]), in three patients it exceeded 10 years, in the rest it ranged from 1 to 8 years. Infectious and lymphoproliferative diseases, monogenic AIDs (CAPS, TRAPS, and HIDS) were excluded from all patients at the prehospital stage. The referral diagnosis for all of them was Still 's disease in adults. Clinical manifestations of the disease in all patients included fatigue, lethargy, fatigue, rash, and fever. In all patients, skin elements were urticular and were accompanied by itching in 6 (37.5%) patients. Bone pain was observed in 12 (70.6%) patients; arthralgias, in 16 (94.1%); arthritis, in 9 (52.9%); myalgia, in 7 (41.2%); and weight loss, in 4 (23.5%). Lymphadenopathy was detected in 6 (35.3%) patients; enlarged liver, in 6 (35.3%); pericarditis, in 4 (23.5%); angioedema, in 6 (35.3); redness and dryness in the eyes, in 3 (17.6%); sore throat, in 2 (11.8%); abdominal pain, in 1 (5.9%), distal polyneuropathy, in 2 (11.8%); paraesthesia, in 1 (5.9%); and chondritis of the auricles, in 1 (5.9%). Monoclonal gammopathy was detected in all patients with a secretion level of 2.9-15.1 g/L: IgMk (n = 10, 64.7%), less often IgMλ (n = 2), IgGk (n = 2), IgGλ (n = 1), and IgAλ (n = 1). Ben-Jones protein was not detected in any of them. All patients had an increased level of ESR and CRP. Before inclusion in the study, 16 patients received GCs (94.1%) with a temporary effect that disappeared with dose reduction or cancellation. Seven patients received cDMARDs, including methotrexate (5), hydroxychloroquine (2), and cyclophosphamide (1). All patients received NSAIDs and antihistamines, as well as biologics, including the anti-B-cell drug rituximab (1), monoclonal ABs to IgE omalizumab (2, 1 without effect and 1 with partial effect), IL-1i canakinumab (n = 10, 58.8%) subcutaneously once every 8 weeks, and anakinra (n = 4, 23.5%) subcutaneously daily. The duration of taking anakinra, which was prescribed in the test mode, ranged from 1 week to 2.5 months with a further switch to canakinumab in 3 patients. The duration of taking canakinumab at the time of analysis ranged from 7 months to 8 years. Against the background of treatment with IL-1i, 10 out of 11 (90.9%) patients received a complete response in terms of the clinical manifestations of the disease and a decrease in the level of ESR and CRP within a few days. In one patient, a partial response to the administration of anakinra was detected; however, after switching to canakinumab, the effect of treatment was finally lost. One patient received IL-6i for 8 months with an incomplete effect and a positive dynamics after switching to anakinra. Thus, anakinra was initially prescribed to four patients and changed to canakinumab in two of them; canakinumab was started as the first drug in seven patients. Treatment with anakinra was continued in two patients; with canakinumab, in nine patients. In one patient, due to the persistent absence of relapses, the interval between canakinumab injections was increased to 5 months without signs of reactivation; however, subsequently, against the background of stress and relapses of the disease, the intervals were reduced to 4 months. A healthy child was born by the same patient on the background of treatment. The tolerability of therapy was satisfactory in all patients, no SAEs were noted. SchS is a rare multifactorial/non-monogenic AID that should be differentiated from a number of rheumatic diseases and other AIDs. The onset in adulthood, the presence of recurrent urticarial rashes in combination with fever and other manifestations of a systemic inflammatory response are indications for examination for monoclonal secretion. The use of short- or long-acting IL-1i is a highly effective and safe option in the treatment of such patients.

Reactive Oxygen Species Modulate Th17/Treg Balance in Chlamydia psittaci Pneumonia via NLRP3/IL-1ß/Caspase-1 Pathway Differentiation.

Chlamydia psittaci pneumonia (CPP) is a lung disease caused by the infection with the Chla-mydia psittaci bacterium, which can lead to severe acute respiratory distress syndrome and systemic symptoms. This study explored the specific mechanisms underlying the impact of reactive oxygen species (ROS) on the Th17/Treg balance in CPP. The levels of ROS and the differentiation ratio of Th17/Treg in the peripheral blood of healthy individuals and CPP patients were measured using ELISA and flow cytometry, respectively. The association between the ROS levels and Th17/Treg was assessed using Pearson correlation analysis. The ROS levels and the Th17/Treg ratio were measured in CD4+ T cells following H2O2 treatment and NLRP3 inhibition. The effects of H2O2 treatment and NLRP3 inhibition on the NLRP3/IL-1ß/caspase-1 pathway were observed using immunoblotting. Compared to the healthy group, the CPP group exhibited increased levels of ROS in the peripheral blood, an elevated ratio of Th17 differentiation, and a decreased ratio of Treg differentiation. ROS levels were positively correlated with the Th17 cell proportion but negatively correlated with the Treg cell proportion. The ROS levels and NLRP3/IL-1ß/caspase-1 expression were up-regulated in CD4+ T cells after H2O2 treatment. Furthermore, there was an increase in Th17 differentiation and a decrease in Treg differentiation. Conversely, the NLRP3/IL-1ß/caspase-1 pathway inhibition reversed the effects of H2O2 treatment, with no significant change in the ROS levels. ROS regulates the Th17/Treg balance in CPP, possibly through the NLRP3/IL-1ß/caspase-1 pathway. This study provides a new perspective on the development of immunotherapy for CPP.

Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19.

BACKGROUND: We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. RESULTS: Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030). CONCLUSIONS: The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.