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关键词： canakinumab   colchicine   familial Mediterranean fever   IL-1 blockers   PAPASH syndrome  

关键词： IL-17C   PPP6C   psoriasis   SMURF2   ubiquitination  

摘要： Psoriasis, a persistent inflammatory skin condition, affects approximately 2%-3% of the world's population. Increased IL-17C levels are noted in psoriatic lesions, alongside IL-17's ability to diminish protein phosphatase 6 catalytic subunit (PPP6C) expression in keratinocytes. Additionally, SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) facilitates the degradation of specific substrates through ubiquitination. However, the precise mechanisms of action involving IL-17C, SMURF2, and PPP6C in psoriasis remain unclear. Therefore, this study aims to delve into how IL-17C, SMURF2, and PPP6C contribute to psoriasis development. A psoriasis mice model was established using 5% imiquimod cream. And the expression of IL-17C, SMURF2, and PPP6C was tested. Further, an investigation was conducted using experimental techniques such as CCK-8, flow cytometry, colony formation assay, ELISA, qRT-PCR, western blot assay, co-immunoprecipitation, and ubiquitination assays. Employing both lentiviral transfection and plasmid transfection methods, an in-depth investigation was conducted into the contributions of IL-17C, SMURF2, and PPP6C to psoriasis. The results showed that the IL-17C, Keratin 17 and SMURF2 were increased, and PPP6C was decreased in psoriasis mice model. Further, IL-17C enhanced the cell viability of human epidermal keratinocytes (HaCaT), induced inflammatory responses, and upregulated SMURF2 and Keratin 17 expression. When SMURF2 was silenced, the effects of IL-17C on HaCaT cells were significantly inhibited. Moreover, SMURF2 interacted with PPP6C, promoting its ubiquitination and degradation. Overexpression of SMURF2 further enhanced the effects of IL-17C on HaCaT cells by targeting PPP6C. In conclusion, our study uncovered the upregulation of SMURF2 mediated by IL-17C, leading to psoriasis-like alterations in keratinocytes through the promotion of PPP6C ubiquitination. This novel finding not only provides crucial insights into the molecular mechanisms of psoriasi

关键词： IL-7   autoimmune diseases   cytokine   T cells   B cells   therapeutic targets  

摘要： Interleukin-7 (IL-7) is a pleiotropic cytokine that plays a crucial role in the development, homeostasis, and function of the immune system. Growing evidence has demonstrated that IL-7 is involved in the pathogenesis of various autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D) and multiple sclerosis (MS). This review aims to summarize the current understanding of the role of IL-7 in autoimmune diseases, focusing on its mechanisms of action, implications for disease progression, and potential therapeutic applications. Produced by stromal cells, IL-7 binds to IL-7 receptor (IL-7R) on diverse immune cells. It is crucial for T cell development, survival, and proliferation. In autoimmune diseases, it activates and expands autoreactive T cells and influences B cell function, potentially leading to autoantibody production. The review further delves into the role of IL-7 in different autoimmune diseases. In RA, elevated IL-7/IL-7R promotes memory T cell survival, cytokine production, and influences B cells and monocytes to contribute to inflammation and joint damage. In SLE, elevated soluble form of IL-7R is associated with disease activity, promoting the survival of autoreactive T cells and enhancing the production of pro-inflammatory cytokines. In MS, genetic variations in the IL-7R gene are linked to disease susceptibility, and IL-7 impacts the survival and differentiation of T cell subsets involved in multiple sclerosis pathogenesis. For T1D, IL-7 affects the function of immune cells that attack pancreatic beta cells. Given its central role in autoimmune processes, targeting the IL-7/IL-7R axis holds great therapeutic potential. By modulating IL-7 signaling, it may be possible to restore immune tolerance, reduce the activation of autoreactive immune cells, and alleviate disease symptoms. Understanding the complex mechanisms of IL-7 in autoimmune diseases is essential for the development of effective and ta

关键词： IL-17 receptor   IL-17RB   IL-17E (IL-25)   social interaction   autism   cytokine receptor   IL-17A  

摘要： Cytokines interact with their receptor complexes to orchestrate diverse processes-from immune responses to behavioral modulation. Interleukin-17A (IL-17A) mediates protective immune responses by binding to IL17 receptor A (IL-17RA) and IL-17RC subunits. IL-17A also modulates social interaction, yet the role of cytokine receptors in this process and their expression in the brain remains poorly characterized. Here, we mapped the brain-region-specific expression of all major IL-17R subunits and found that in addition to IL-17RA, IL-17RB-but not IL-17RC-plays a role in social behaviors through its expression in the cortex. We further showed that IL-17E, expressed in cortical neurons, enhances social interaction by acting on IL-17RA-and IL17RB-expressing neurons. These findings highlight an IL-17 circuit within the cortex that modulates social behaviors. Thus, characterizing spatially restricted cytokine receptor expression can be leveraged to elucidate how cytokines function as critical messengers mediating neuroimmune interactions to shape animal behaviors.

关键词： Cell migration/adhesion   Immunotherapy   Neuroscience   Oncology   T cells  

摘要： The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies.

关键词： IL-6/JAK/STAT3信号通路   抑制剂   中药香附   倍半萜   抗癌  

摘要： IL-6/JAK/STAT3信号通路与癌症和炎症性疾病密切相关，在多种人类肿瘤细胞种被发现异常活化，是相关药物研发的重要靶点，靶向该通路的抑制剂临床已成功用于相关疾病的治疗.为了发现IL-6/JAK/STAT3通路抑制剂，利用脂质体转染和报告基因检测法构建了SIE-荧光素酶基因稳定表达的细胞系并建立了相应的通路抑制剂筛选模型，对我们从中药香附中分离得到的倍半萜类化合物进行了活性筛选，首次发现了4个对IL-6诱导的JAK/STAT3信号通路活化有抑制作用的倍半萜类化合物（1～4），其IC50值在58.18～170.06 μmol/L之间.应用细胞免疫荧光和蛋白免疫印迹法考察了活性化合物对IL-6诱导活化的JAK/STAT3通路中关键蛋白的调控作用，发现化合物1～4主要通过下调磷酸化JAK2蛋白水平，进而阻碍STAT3蛋白从细胞质转位进入细胞核，从而发挥对信号通路的抑制作用.本研究为中药香附的功效物质研究提供了理论支持，也为香附倍半萜类化合物作为抗炎或抗癌药物的研发打下了理论基础.

关键词： IL-16   Sarcopenia   Inflammaging   Cytokines   Muscle atrophy  

摘要： Background In this study, we aim to explore the roles of IL-16 in sarcopenia based on older orthopedic patients and animal research. Methods This clinical research in this study was an observational investigation and included all the older patients with orthopedic trauma admitted to our department between January 2021 and January 2022. Patients were identified with sarcopenia if they have both low hand grip strength (HGS) and low appendicular skeletal muscle mass (ASM). Propensity score matching (PSM) was performed to reduce the bias caused by the co-factors and levels of IL-16 between normal patients and patients with sarcopenia were compared. In animal research, mice were treated with IL-16 to identify the effects of IL-16 on muscle function and muscle mass. Then the sarcopenia models were established and the anti-IL-16 was performed to identify the potential therapeutical effect of targeting IL-16. Results 421 individuals were included in the clinical study, and 77 were identified as sarcopenia. In the matched populations, the serum levels of IL-16 of individuals with low HGS, ASM, and sarcopenia were significantly higher than normal individuals (all p < 0.001). The mice treated with IL-16 showed significantly impaired muscle function and physical performance and loss of muscle mass. Using anti-IL-16 antibodies may rescue the sarcopenia traits caused by botulinum toxin type A. Conclusion Individuals with high levels of IL-16 may have a significantly high risk of sarcopenia. IL-16 impairs muscle function and physical performance and leads to muscle atrophy in mice, and these effects could be reduced by targeting IL-16.

关键词： Coronary microcirculation   Ischaemia-reperfusion injury   Interleukin-36   Hyperglycaemia   Inflammation  

摘要： Following myocardial infarction (MI), patients with type 2 diabetes mellitus (T2DM) have poorer prognosis which may be linked to increased susceptibility of coronary microvessels to injury. Interleukin-36 (IL-36) may mediate this injury but its role in the microcirculation of the chronically hyperglycaemic injured heart is unknown. Intravital and laser speckle imaging of the anaesthetised mouse beating heart evaluated the impact of a 16-week high fat diet (HFD)-induced hyperglycaemia +/- myocardial ischaemia-reperfusion injury (IR) injury on coronary microvessels. Neutrophil/platelet recruitment, neutrophil extracellular trap formation, cellular necrosis, vascular leakage, vascular tonal changes, functional capillary density, overall ventricular perfusion and levels of circulating inflammatory cytokines were assessed alongside the vasculoprotective ability of an IL-36 receptor antagonist (IL-36Ra). Whether heightened microvessel damage in injured HFD mice was permanent or reversible was investigated after normalising hyperglycaemia through diet reversal (DR). Microcirculatory events assessed were perturbed basally in HFD mice and further after injury. IL-36Ra mitigated these effects and improved infarct size. DR was also beneficial, decreasing neutrophil recruitment to levels below those seen in untreated mice. Mechanistically, benefits of both IL-36Ra and DR could be explained by decreased endothelial oxidative stress and VCAM-1 expression and possibly by raised levels of IL-4/IL-13. Basal changes in chronically hyperglycaemic coronary microvessels that are heightened in the aftermath of reperfusion may explain the poorer outcomes in MI patients with T2DM. These findings are the first to highlight the specific benefits of IL-36 inhibition and reversing hyperglycaemia through dietary modification on the coronary microcirculation in a preclinical model of T2DM.

摘要： Despite the proven clinical activity of checkpoint inhibitors (ICIs) in several cancer indications, frequent occurrence of primary and secondary resistance reduces their overall effectiveness. Development of ICI resistance has been attributed mainly to genetic or epigenic alterations that affect the tumor antigen presentation machinery leading to diminished anti-tumor immune responses. There is an urgent need for new approaches which can either re-sensitize resistant tumors to the ICIs or engage alternate immune pathways to inhibit tumors. Intratumoral delivery of nanoparticle encapsulated murine IL-12 (mIL-12) mRNA induces powerful anti-tumor immune responses in murine tumor models and the human version of this drug results in objective responses in patients with advanced disease. Here, we tested the efficacy of mIL12 mRNA as a single agent and in combination with anti-PD-L1 antibodies in ICI sensitive Yummer1.7 melanoma and MC38 colorectal murine tumors and in ICI resistant, β2-microglobulin ( ) knockout versions of these models. mIL12 mRNA monotherapy was sufficient to cause complete responses (CRs) in ≥ 60% of both ICI sensitive or resistant Yummer1.7 melanoma and MC38 colorectal carcinoma tumors. The mIL12 mRNA treatment resulted in potent upregulation of T 1 type cytokines and chemokines. A reduction in number of Tregs, increase in numbers and activation state of both cytotoxic T cells (CTLs) as well as tumor associated macrophages (TAMs) was observed indicating enhanced anti-tumor, cell-based immune responses in the tumor microenvironment. This mIL-12 induced concerted immune activation was associated with a robust killing and phagocytosis of tumor cells resulting in durable CRs. These observations suggest that intratumoral IL12mRNA therapy may benefit patients with ICI resistant cancers.

关键词： Cell death  

摘要： Psoriasis, a chronic inflammatory skin disorder, remains challenging to treat due to poor skin barrier penetration, limited efficacy, and adverse effects of current therapies. Natural plant-derived extracellular vesicle-like particles (EVPs) have emerged as biocompatible carriers for bioactive molecules. Among various medicinal plants screened, Perilla frutescens leaf-derived EVPs (PLEVPs) exhibited strong anti-inflammatory and antioxidant effects. By incorporating PLEVPs into a hydrogel formulation, we enhanced their stability, retention at psoriatic lesions, and transdermal delivery efficiency. In vivo studies demonstrated that the PLEVPs markedly alleviated psoriasis symptoms in both preventive and therapeutic mouse models, outperforming conventional treatments. This effect was attributed to reduced oxidative stress, modulation of Treg cells, and promotion of keratinocyte apoptosis. Transcriptomic analysis revealed enrichment of the interleukin-17 (IL-17) signaling pathway, a major driver of psoriasis, while small RNA sequencing identified pab-miR396a-5p, an endogenous microRNA (miRNA) within PLEVPs, as a key regulator. Mechanistic studies showed that pab-miR396a-5p targets the 3 '-untranslated region of plant heat shock protein 83a, a homolog of mammalian heat shock protein 90, leading to the suppression of nuclear factor-kappa B and Janus kinase/signal transducers and activators of transcription signaling, inhibiting the IL-17 signaling pathway. Validation using lipid nanoparticles encapsulating pab-miR396a-5p mimics confirmed comparable therapeutic effects. This study highlights the potential of plant-derived EVPs as carriers of endogenous miRNAs, enabling interkingdom communication and offering a scalable platform for psoriasis therapy.