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摘要： Hematopoietic stem cells (HSCs) readily recover from acute stress, but persistent stress can reduce their viability and long-term potential. Here, we show that the nuclear factor of activated T cells 5 (NFAT5), a transcription modulator of inflammatory responses, protects the HSC pool under stress. NFAT5 restrains HSC differentiation to multipotent progenitors after bone marrow transplantation and bone marrow ablation with ionizing radiation or chemotherapy. Correspondingly, NFAT5-deficient HSCs fail to support long-term reconstitution of hematopoietic progenitors and mature blood cells after serial transplant. Evidence from competitive transplant assays shows that these defects are HSC intrinsic. NFAT5-deficient HSCs exhibit enhanced expression of type 1 interferon (IFN-1) response genes after transplant, and suppressing IFN-1 receptor prevents their exacerbated differentiation and cell death after reconstitution and improves long-term regeneration potential. Blockade of IFN-1 receptor also prevented the overdifferentiation of NFAT5deficient HSCs after bone marrow ablation. These findings show that long-term IFN-1 responses to different hematopoietic stressors drive HSCs toward more differentiated progenitors, and that NFAT5 has an HSC-intrinsic role, limiting IFN-1 responses to preserve reconstitution potential. Our identification of cell-intrinsic mechanisms that strengthen the resistance of HSCs to stress could help to devise approaches to protect long-term stemness during the treatment of hematopoietic malignancies.

关键词： bispecific antibody   IL-17A   IL-36R   skin inflammation   skin fibrosis  

摘要： Antibody drugs targeting single inflammatory cytokines have revolutionized the treatment of immune-mediated inflammatory diseases. To investigate whether dual targeting interleukin-17 (IL-17) and IL-36 enhances anti-inflammatory activity, bispecific Ab HB0043 was generated by linking the single chain fragment variables (scFvs) from humanized anti-IL-36R antibody (HB0034) to the C-terminus of the heavy chain of anti-IL-17A IgG1 (HB0017) Fc using a flexible peptide linker. HB0043 largely maintained the binding affinities and biological activities of the two parent monoclonal antibodies (mAbs) in vitro. IL-17 and IL-36 cooperated to amplify the expression of pro-inflammatory and pro-fibrotic genes in normal human dermal fibroblasts (NHDF). However, HB0043 more effectively blocked IL-6 and IL-8 production in NHDF stimulated by IL-17A and IL-36 compared to two monoclonal antibodies. In a mouse model of Oxazolone (OXA)-induced atopic dermatitis and Imiquimod (IMQ)-induced skin inflammation, administration of both anti-IL17A mAb HB0017 and anti-mouse IL-36R surrogate antibody HB0034SA showed improved effectiveness in alleviating skin thickening and inflammation based on histological assessment. Further, in cynomolgus monkeys, HB0043 showed no enhanced target-related toxicity compared with the two parental mAbs in vivo and with a moderate increase in production of anti-drug antibodies. Together, dual blockade of IL-17A and IL-36R in the form of a bispecific antibody may have advantages in blocking the overlapping and non-overlapping functions of these two cytokines in skin inflammation that could not optimally be curtailed with single mAbs. In conclusion, as monotherapy may reach therapeutic celling for certain difficult-to-treat inflammatory and fibrotic diseases, dual targeting could potentially pave a way to combat these diseases.

关键词： TNF-α   肺炎克雷伯菌肺炎   细菌耐药  

摘要： 目的 研究外周血肿瘤坏死因子-α(tumornecrosis factor-α，TNF-α)在肺炎克雷伯菌肺炎中的诊断和治疗意义。方法 选取2023年1～12月某院收治的120例肺炎克雷伯菌肺炎患者，其中有57例肺炎克雷伯菌肺炎患者为轻度感染组，63例中重度感染组，将两组作为观察组。另选取同时期健康体检者55名作为对照组，研究3组的TNF-α、CRP（C-reactive protein，CRP）、PCT（Procalcitonin，PCT）与肺炎严重程度的相关性。同时对比轻度与中重度感染组在治疗前及治疗期间第0、12、24、48、72、96 h的TNF-α、CRP、PCT的变化情况，分析三者在肺炎克雷伯菌肺炎中的诊疗价值。结果 对照组、轻度感染组、中重度感染组的TNF-α、CRP均具有正相关性，3组之间的差异具有统计学意义（P＜0.05），轻度感染组与中重度感染组PCT之间差异具有统计学意义（P＜0.05），轻度感染组与对照组PCT之间差异无统计学意义（P＞0.05）；TNF-α、CRP、PCT在轻度感染组中分别在第12 h、第24 h、第24 h达到峰值区域，分别在第24 h、第48 h、第72 h下降至正常水平，TNF-α、CRP、PCT在中重感染组中分别在第12 h、第24 h、第12 h达到峰值区域，分别在第48 h、第72 h、第72 h下降至正常水平。同时受试者工作特征曲线（Receiver Operating Characteristic Curve，ROC）曲线显示，TNF-α、CRP 、PCT的曲线下面积（area under curve，AUC）分别为0.8605、0.785 7、0.799 0。结论 TNF-α、CRP、PCT表达水平与肺炎克雷伯菌肺炎严重程度具有正相关性，TNF-α相比PCT、CRP在肺炎克雷伯菌肺炎诊断和预后中具有重要的临床意义。

关键词： Aronia berry   Dietary anthocyanins   Inflammation   Myogenesis capacity   Inflammatory atrophy  

摘要： This study investigates the effects of Aronia berries, their primary anthocyanins and other second metabolites-mimicking dietary anthocyanin consumption-on enhancing muscular myogenesis under chronic inflammation. Murine muscle satellite cells (MuSCs) were cultured ex vivo, allowing for expansion and differentiation into myotubes. Myogenic differentiation was disrupted by TNF alpha at both early and terminal stages, with treatment using Aronia berries applied at physiologically relevant concentrations alongside TNF alpha. The results demonstrated that Aronia berries treatments, particularly phenolic metabolites, significantly stimulated the proliferative capacity of MuSCs. Furthermore, Aronia berries treatment enhanced early-stage myogenesis, marked by increased MymX and MyoG expression and nascent myotube formation, with metabolites showing the most pronounced effects. Aronia berry powder and individual anthocyanins exerted milder regulatory effects. Similar trends were observed during terminal differentiation, where Aronia berries treatment promoted myotube growth and inhibited TNF alpha-induced inflammatory atrophic ubiquitin-conjugating activity. Additionally, the secondary metabolites of Aronia berries significantly prevented muscle-specific ubiquitination in the dexamethasone-induced atrophy model. Overall, the treatment with Aronia berries enhanced myogenesis in a cellular model of chronic muscular inflammation, with Aronia-derived metabolites showing the strongest response, likely through TLR4/NF-kappa B modulation. In this case, enhanced regeneration capacity and anti-atrophy potential were associated with TLR4/NF-kappa B modulation.

摘要： BACKGROUND:Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines IL-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A. OBJECTIVES:To further investigate the roles of IL-17A and IL-17F in HS pathogenesis. METHODS:RNA sequencing was conducted on skin biopsies taken at baseline and after treatment at Week 12 of the phase 2 proof of concept study of bimekizumab in patients with moderate to severe HS. Differentially expressed genes were identified between baseline lesional and non-lesional samples and between lesional samples before and after bimekizumab treatment to describe molecular disease mechanisms and treatment *** hair follicular keratinocytes (HHFK) were cultured and treated with the supernatant of stimulated Th17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNA sequencing (RNAseq). Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays. RESULTS:RNAseq revealed that the most prominently upregulated genes within HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. Extent of reduction in gene expression was dependent on HiSCR50 fulfilment. In vitro, dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs compared to IL-17A or IL-17F inhibition alone. In situ hybridisation revealed IL-17A and IL-17F producing cells in HS lesions can lack IL-23R and IL-1β could induce IL-23-independent IL-17F expression in vitro. Furtherm

关键词： inflammasome   monocytes   MxA   NLRP3   red blood cells   systemic lupus erythematosus   type I interferon  

摘要： Opsonization of red blood cells that retain mitochondria (Mito⁺ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito⁺ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors’ (RLRs) sensing of Mito⁺ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito⁺ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the NLRP3 inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease. © 2024 Elsevier Inc.

摘要： In a Science paper, Park et al. identified interleukin (IL)-1a as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1a production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice.

关键词： dapsone hypersensitivity syndrome   severe cutaneous adverse reactions   TNFR   TNF-alpha   VISTA  

摘要： BackgroundSevere cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life-threatening conditions with a mortality of 4%-20%. The clinical application of tumor necrosis factor-alpha (TNF-alpha) antagonist improves the outcome of some SCARs patients;however, this is complicated by the elusive and varied *** investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to *** clarify the precise process and optimize the therapy regimen of SCARs, we performed single-cell sequencing, in vitro functional and clinical analysis of patients with *** observed that TNF-alpha breaks drug-specific T-cell tolerance by inhibiting the expression of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA). Furthermore, TNF-alpha generated a positive feedback loop in the early phase of drug-specific T-cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF-alpha cytokine expression. In contrast, this pathway of TNF-alpha-VISTA signaling did not operate in memory effector T cells. Drug-specific memory effector T-cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF-alpha antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF-alpha antagonists significantly improved outcomes in SCARs *** findings defining feedback regulation of VISTA and Treg cells by TNF-alpha in different stages of the drug-specific T-cell response and, indicate that a Treg agonists, instead of TNF-alpha antagonists, could be used for treatment of patients with progressive SCARs.

关键词： Methotrexate   Dabigatran   Inflammation   Coagulation   Endothelial dysfunction   Hepatotoxicity  

摘要： This study examines Dabigatran's (Dab) capacity to mitigate methotrexate (MTX)-induced coagulation disorders and endothelial dysfunction, while exploring its effects on oxidative stress and inflammatory pathways (NF-kB/IL-1 beta/MCP-1, TLR4/NLRP3) in reducing hepatotoxicity. Rats were assigned to four groups: a control group receiving saline intraperitoneally (i.p.);an MTX group with a single MTX dose (20 mg/kg, i.p.) to induce hepatotoxicity;and two pretreatment groups receiving Dab orally at 15 mg/kg and 25 mg/kg for seven days before and 4 days after MTX administration. MTX-treated rats showed significant increases in liver enzymes (ALT, AST, ALP) and reductions in antioxidant enzymes (SOD, GSH), along with elevated coagulation parameters (tissue factor (TF), thrombin, fibrin, plasminogen activator inhibitor-1 (PAI-1)), leading to coagulation disorders. Endothelial dysfunction was evident with reduced eNOS expression, while inflammation increased through elevated iNOS, ICAM-1, and pro-inflammatory cytokines (MPO, NF-kB, TNF-alpha, IL-1 beta, MCP-1), alongside activation of the TLR4/NLRP3 inflammasome pathway and decreased IL-10 (p < 0.05). Immunohistochemistry revealed increased cytochrome c and caspase-3 expression, with histopathological damage. Dabigatran mitigated these effects, downregulating liver enzymes, modulating coagulation factors, restoring eNOS levels, and reducing histopathological and inflammatory markers. Dabigatran demonstrates significant therapeutic potential in alleviating methotrexate-induced hepatotoxicity through its antioxidant, anti-inflammatory, anticoagulant, and anti-apoptotic effects. Its regulation of coagulation parameters and endothelial function suggests a protective role against tissue damage, warranting further investigation.

关键词： 脑组织   出血   白介素-10   神经发生   神经功能   修复  

摘要： 目的 探讨白介素-10(IL-10)对脑出血雄性小鼠神经功能的影响及其可能作用机制。方法 应用Ⅶ型胶原酶注射法制备脑出血（ICH）模型，于造模后第1、3、7、14、21、28 d分别进行神经功能缺失评分和感觉运动功能检测。于造模后第3、7、14 d取脑组织，采用免疫荧光法测定神经干细胞增殖和分化标记物的表达情况。结果 与野生型（WT）组比较，IL-10基因敲除（KO）组在ICH术后第7、14、21 d的神经功能缺失评分较高（P<0.05)；转角实验和前肢踏空实验显示，ICH术后第7、14 d KO组向右转向频次和踏空失误率高于WT组（P<0.05）；前肢悬挂实验显示，ICH术后第7、14 d KO组悬挂时间低于WT组（P<0.05）。免疫荧光染色实验显示，ICH术后KO组的EDU、Ki67阳性细胞明显少于WT组（P<0.001）;ICH术后KO组的NeuN/EDU双标阳性细胞、GFAP/EDU双标阳性细胞少于WT组（P<0.001）。结论 IL-10对脑出血雄性小鼠神经功能存在影响；IL-10缺乏可能通过抑制脑内神经干细胞的神经发生，延缓脑出血后所致感觉和运动功能损伤的修复。