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关键词： Immunosuppression   Macrophages   MSCs  

摘要： Background & AimThe immunosuppressive activity of human mesenchymal stromal cells (MSCs) is central to the approved and investigational use of MSC therapy in inflammatory conditions such as GvHD. External factors like cytokines and other molecules encountered in the disease microenvironment significantly influence MSC immunosuppressive function. The obese microenvironment including elevated levels of serum free fatty acids, specifically palmitate, have the potential to affect MSC therapy. For T cell suppression, it has already been shown that exposure to palmitate impairs the ability of MSCs to carry out their function. However, we do not yet understand the effects of palmitate on MSC immunosuppression of macrophages. This study focused on investigating the influence of palmitate on MSC functional capacity to suppress macrophages and to elucidate the mechanisms of action at play. MethodologyWe used peripheral blood from healthy control and patients with obesity to investigate the immunosuppressive capacity for MSCs or MSCs exposed to plamitate in vitro. Following exposure to palmitate, the capacity for MSCs to alter human monocyte derived macrophage (MDM) production of TNFa and IL-10 and phenotype following LPS stimulation were investigated. Moreover, chemical anatagonists, neutralising antibodies and a biologically active, cell-permeable ceramide analog were used to uncover the mechanisms of action. ResultsPalmitate exposure significantly increased expression of the MSC immunomodulatory factors ptgs2, il-6, ccl2 and angptl4. Palmitate exposed MSCs had significantly modulated LPS stimulated human MDMs leading to decreased TNFα and increased IL-10 production by MDMs. Using a neutralising antibody, we identified that enhanced suppression mediated by palmitate exposed MSCs involved CCL2. Using the biologically active, cell-permeable ceramide analog C2 as well as the cermide synthases inhibitor (fumonisin B1), we showed that palmitate enhanced MSC immunomodulation of MD

关键词： cytokines   interleukin 1 beta   matrix metalloproteinases   periodontitis   saliva   systematic review  

摘要： Background and Objective: Proinflammatory cytokines and enzymes responsible for tissue destruction are important in the development of periodontitis. This study compared salivary concentrations of interleukin-1 beta (IL-1 beta), matrix metalloproteinases (MMP-8), and (MMP-9) in individuals with and without periodontitis to evaluate their diagnostic utility as potential biomarkers. Materials and Methods: A comprehensive search was performed across PubMed, Scopus, ScienceDirect, and Google Scholar, supplemented by manual searches in relevant journals up to January 2024. Eligibility criteria focused on human studies with defined diagnostic criteria for periodontitis and saliva samples analyzed for IL-1 beta, MMP-8, and MMP-9. Data were extracted to compare salivary levels of these markers between periodontitis patients and healthy controls. The Joanna Briggs Institute tool was used to evaluate the risk of bias and quality of the included studies. Statistical analysis employed a random effects model to calculate standardized mean differences and assess heterogeneity and publication bias. Results: The search yielded 122 articles, with 27 meeting the inclusion criteria. Fifteen percent of these studies presented a moderate risk of bias, while the remaining 85% exhibited a low risk of bias. The meta-analyses indicated significantly higher levels of IL-1 beta, MMP-8, and MMP-9 in the saliva of subjects with periodontitis compared to healthy individuals: IL-1 beta: Standardized Mean Difference (SMD) = 163.29 (95% CI = 104.64-221.95), p < 0.001;MMP-8: SMD = 282.22 (95% CI = 209.68-354.77), p < 0.001;MMP-9: SMD = 311.85 (95% CI = 179.64-444.05), p < 0.001. Conclusion: Elevated salivary levels of IL-1 beta, MMP-8, and MMP-9 are linked to periodontitis.

关键词： EPA   DHA   Myogenic IL-6   Lipid metabolism   TRPV1/Ca2+   AMPK/STAT3  

摘要： Lipid metabolism disorder serve as a critical starting point for the development of chronic non-communicable diseases (NCDs). Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) are known for their lipid-lowering properties, but few studies have revealed their differences from the perspective of skeletal muscle endocrinology. Myogenic IL-6 has garnered significant attention for its role in energy distribution. The primary aim of this study was to investigate the effects and mechanisms of EPA and DHA on myogenic IL-6 and lipid metabolism disorders in mice, and to clarify the association between the alleviation of lipid metabolism disorders and myogenic IL-6 mediated by EPA/DHA. We found that EPA and DHA not only prevented high-fat diet- induced lipid metabolism disorders, but also up-regulated the expression of myogenic IL-6 by activating TRPV1/Ca2+ signaling in skeletal muscle. However, the lipid metabolism prevention effect mediated by EPA was weakened after knockout gene of myogenic IL-6, with its body weight and body fat increased and a large amounts of lipid deposited in the blood, liver, and adipocytes. Meanwhile, there no significantly differences of AMPK/STAT3 signaling in adipose tissue between groups after knockout gene of myogenic IL-6. Based on the results above, we concluded that EPA and DHA can stimulate the production of myogenic IL-6 through TRPV1/Ca2+ signaling in skeletal muscle. The prevention effect of lipid metabolism disorders by EPA, but not DHA, relies on myogenic IL-6, with the underlying mechanism may involving the enhancement of AMPK/STAT3 signaling mediated by myogenic IL-6 in adipose tissues. (c) 2024 Published by Elsevier Inc.

关键词： xMAP technology   CDC   Anti-HLA antibodies   Waiting list   Kidney transplant outcomes  

摘要： Background: Differences in sensitivity and specificity between the techniques used for the detection of anti-HLA antibodies before kidney transplantation (KT) can lead to contradictory results that influence patients' management. Our aim is to analyse whether the technique used, based on complement-mediated-cytotoxicity (CDC) or on microsphere fluorimetry (xMAP), conditions the waiting time until transplantation and its results. Methods: We performed a retrospective cohort study of the KT performed in our centre from 2006 to 2018 whose pre-transplant anti-HLA specificity determination and definition of prohibited antigens was performed by CDC (2006-2011) or by xMAP (2012-2018). Living donor KT recipients were excluded. The influence of each technique on the time on the waiting list and on the outcome of kidney transplantation was analysed, using as indicators the initial function of the graft, the rate of humoral rejection and graft survival. Results: During the period of the study, 622 patients were included (264 were studied by CDC and 358 by xMAP). Recipient and donor age was higher in the xMAP group (p < 0.001). Additionally, most sensitised patients were in the xMAP group (p < 0.001). However, they received a KT earlier. There were no differences in the rate of acute humoral rejection between groups. Nevertheless, graft survival was better in the xMAP group. Conclusions: The introduction of the xMAP technique in our centre has meant an improvement in terms of accessibility to transplantation and the initial management of the patient. However, it does not ameliorate the indicators of graft rejection.

关键词： Psoriasis   Psoriatic arthritis   IL-17   MMP-3   IL-33   Gene expression  

摘要： This study aimed to compare gene expression levels of biomarkers of inflammation, bone damage and cartilage damage (IL-17, IL-33, MMP-3) in psoriasis (PsO) and psoriatic arthritis (PsA) patients with healthy controls and to examine the relationship between changes in expression levels and disease activity. PsO and PsA patients and healthy volunteers were included in the study. Gene expression levels of IL-17, MMP-3 and IL-33 proteins were measured in blood samples. The severity of PsO disease was assessed by PASI, and the severity of PsA disease was assessed by DAS28 CRP and BASDAI. The study included 25 PsO patients (10 women, 15 men), 23 PsA patients (16 women, 7 men) and 26 healthy controls (18 women, 8 men). The disease duration of PsO patients was 12.2 +/- 7.9 years and the PASI score was 9.8 +/- 6.2. The disease duration of PsA patients was 9.6 +/- 9.1 years, 12 patients had axial, and 11 patients had peripheral features. BASDAI score of axial patients was 3.5 +/- 1.5 and DAS28 CRP score of peripheral patients was 3.80 +/- 1.8. The results revealed that IL-17, IL-33 and MMP-3 gene expression levels were higher in PsO and PsA patients than in healthy controls, but these expression levels were not significantly associated with disease activity. However, a significant correlation was found between IL-33 gene expression level and PASI score in PsO patients (P < 0.001).

关键词： Loteprednol etabonate   NLRP3 inflammasome   IL-1 beta   Pyroptosis   Sepsis   Colitis  

摘要： Excessive activation of the NLRP3 inflammasome leads to cellular inflammation and tissue damage. Finding an inhibitor of its activation is urgent need for NLRP3 inflammasome-associated inflammatory diseases. In this study, we identified Loteprednol etabonate (LE), a well-known anti-inflammatory drug for ocular conditions, as a potent inhibitor of NLRP3 inflammasome activation through screening an FDA-approved drug library. In cellular models, LE significantly reduced IL-1f) transcription, suppressed NLRP3 inflammasome activation, and finally inhibited the maturation and secretion of IL-1 beta and GSDMD-mediated pyroptosis. Mechanistic investigations showed that LE might inhibit IL-1f) transcription by blocking both NF-kappa B and AP-1 signaling pathways. Furthermore, in mouse models of NLRP3 inflammasome-associated inflammatory diseases, including LPSinduced sepsis and DSS-induced colitis, intraperitoneal injection of LE significantly suppressed inflammatory response and improved mice survival rate. Collectively, these findings identify LE as a novel inhibitor of NLRP3 inflammasome activation, offering a promising therapeutic strategy for the treatment of NLRP3 inflammasomeassociated inflammatory diseases.

关键词： MHC multimer reagents   flow cytometry   TCR  

摘要： Background & Aim Antigen-specific immune responses are central in the natural response towards cancer, infectious diseases and autoimmunity. Engineered transgenic T cells (TCR Ts) pose high therapeutical potential. The precise discovery and analysis of T cell epitopes and the cognate Antigen (Ag)-specific T cells is crucial for cell therapy development, verifying cellular product quality or monitor T cell immune responses in patients. Based on the individual character of Ag-specific T cell responses (MHC restriction), adaptable tools and workflows are required. These tools must be flexible and be tailored to specific cell materials as well as the patients’ genetic background, plus be easily integrated into existing analytical workflows. We show that our novel MHC multimer reagents (MHC MACSimers) can advance cell therapy development from the early discovery stages until quality control (QC) of cellular products and immunomonitoring, by covering the demand for flexibility, robustness and seamless integration into common state-of-the-art TCR T development workflows. Methodology To enable the optimal integration of MHC MACSimers into drug development workflows, they feature: -high flexibility of peptide-specificity, enabling MHC peptide-loading for epitope screening and compatibility with TCR discovery workflows -compatibility with various applications, including magnetic enrichment flow cytometry sorting and multimer-duplex staining -growing ready-to-use collection of peptide-loaded MHC MACSimers for robust and reproducible QC of T cell products Results We demonstrate that MHC MACSimers can reliably detect rare virus- or cancer-specific T cells for both CD4+ and CD8+ subpopulations with a higher signal strength as compared to other MHC multimer reagents. Combining MHC MACSimers with fluorochrome-specific magnetic MicroBeads improves the discovery of peptide/MHC-specific TCRs from low-frequent T cell populations by providing highly enriched pMHC-specific T cell fractio

关键词： antibody-mediated rejection   canakinumab   interleukin 6   kidney transplantation   tocilizumab  

摘要： Interleukin (IL)-6 is a major pro-inflammatory cytokine and central regulator of innate and adaptive immune responses. Clinical trials testing antibodies against IL-6 or its receptors have demonstrated its involvement in the pathogenesis of several autoimmune and inflammatory disorders and in the systemic inflammation and anemia associated to kidney failure and also in kidney allograft rejection. Additionally, the anti-IL-6 receptor antibody tocilizumab and the anti-IL-6 antibody clazakizumab have been studied for the treatment of na & iuml;ve as well as resistant antibody-mediated kidney allograft rejection with mixed results in observational studies and early clinical development. Following promising results with a clazakizumab in a phase 2 placebo-controlled trial, a large phase 3 trial (IMAGINE) was terminated in 2024 for futility at interim analysis. Investigator-initiated clinical development continues in a smaller phase 3 trial testing tocilizumab (INTERCEPT). In this viewpoint article, we evaluate the pathophysiology of IL-6 in antibody-mediated kidney allograft rejection along with the current status of the clinical development of IL-6 targeting therapies for antibody-mediated kidney allograft rejection episodes within the wider frame of IL-6 targeting therapies in kidney failure that are considered the major causes of graft loss in kidney transplantation.

关键词： Osteoarthritis   polyphyllin I   TWIST1   chondrocytes   MMP-3   PPI  

摘要： Background Osteoarthritis (OA) is a chronic joint disease characterized by the degradation of articular cartilage. Polyphyllin I (PPI) has anti-inflammatory effects in many diseases. However, the mechanism of PPI in OA remains *** HC-a cells treated with IL-1 beta were identified by immunofluorescence staining and microscopic observation. The expression of collagen II and DAPI in HC-a cells was detected by immunofluorescence. The effects of gradient concentration of PPI on IL-1 beta-induced cell viability, apoptosis, senescence, and inflammatory factor release were detected by MTT, flow cytometry, SA-beta-Gal assay and ELISA, respectively. Expressions of apoptosis-related genes, extracellular matrix (ECM)-related genes, and TWIST1 were determined by qRT-PCR and western blot as needed. The above-mentioned experiments were conducted again after TWIST1 overexpression in IL-1 beta-induced *** IL-1 beta reduced the number of chondrocytes and the density of collagen II. PPI (0.25, 0.5, 1 mu mol/L) had no effect on cell viability, but it dose-dependently elevated the inhibition of cell viability regulated by IL-1 beta. The elevation of cell apoptosis, senescence and expression of IL-6 and TNF-alpha were suppressed by PPI in a dose-dependent manner. Additionally, PPI reduced the expression of cleaved caspase-3, bax, MMP-3, and MMP-13 and promoted the expression of collagen II. TWIST1 expression was diminished by PPI. TWIST1 overexpression reversed the above-mentioned effects of PPI on *** PPI suppressed apoptosis, senescence, inflammation, and ECM degradation of OA chondrocytes by downregulating the expression of TWIST1.