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关键词： Caspase-8   TNFR1   Duodenal Pathology   T Cell Imbalance   Intestinal Epithelial Layer  

摘要： RIPK1 is a crucial regulator of cell survival, inflammation and cell death. Human RIPK1 deficiency leads to early-onset intestinal inflammation and peripheral T cell imbalance, though its role in alpha beta T cell-mediated intestinal homeostasis remains unclear. In this study, we demonstrate that mice with RIPK1 ablation in conventional alpha beta T cells (Ripk1 Delta CD4) developed a severe small intestinal pathology characterized by small intestinal elongation, crypt hyperplasia, and duodenum-specific villus atrophy. Using mixed bone marrow chimeras reveals a survival disadvantage of alpha beta T cells compared to gamma delta T cells in the small intestine. Broad-spectrum antibiotic treatment ameliorates crypt hyperplasia and prevents intestinal elongation, though villus atrophy persists. Conversely, crossing Ripk1 Delta CD4 with TNF receptor 1 Tnfr1-/- knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of Ripk1 triangle CD4 and Casp8 triangle CD4 fully rescues intestinal pathology, revealing that alpha beta T cell apoptosis in Ripk1 triangle CD4 drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of alpha beta T cells is essential for proximal small intestinal homeostasis. In Ripk1 triangle CD4 mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.

关键词： MHC-II macrophages   tumor-associated macrophage   DNA methylation   monocyte-to-macrophage transition   Arg1 macrophages   prostaglandin E2   EP2   lung metastasis   macrophage differentiation  

摘要： Monocytes differentiate into macrophages (Mops) to facilitate lung metastasis, but the monocyte-to-Mop transition during this process is not well understood. To investigate, we performed bulk RNA sequencing on Mops isolated from the lungs of mice bearing Lewis lung carcinoma tumors and from naive lungs. Our results showed impaired differentiation of monocytes into major histocompatibility complex (MHC) class II+ Mops, with an upregulation of PGE2-inducible genes, including Arg1, in tumor-associated Mops (TAMs). In vitro experiments confirmed that prostaglandin E2 (PGE2) inhibits the differentiation of MHC class II+ Mops while promoting Arg1+ Mops via the E prostanoid 2 (EP2) receptor, accompanied by DNA methylation. Whole-genome bisulfite sequencing revealed that PGE2-EP2 signaling drives the hypermethylation and downregulation of gene sets related to myeloid cells in non-neoplastic tissues. Our study highlights PGE2-EP2-driven DNA methylation in the monocyte-to-TAM transition, suggesting potential therapeutic avenues for lung metastasis.

关键词： immune-related diseases   inflammatory diseases   type III interferon  

摘要： Type III interferons (IFN-lambda), which include IFN-lambda 1 (or interleukin [IL]-29), IFN-lambda 2 (IL-28A), IFN-lambda 3 (IL-28B) and IFN-lambda 4, exert their effects through a unique receptor complex composed of interferon lambda receptor 1 (IFNLR1) and IL-10 receptor subunit beta (IL-10R2). Studies have highlighted their critical role in modulating immune response, particularly in the context of autoimmune diseases, viral infections and cancer. Unlike type I IFNs, which are broadly expressed, IFN-lambda displays a more tissue-specific expression pattern, predominantly acting on epithelial cells and certain immune cell types, such as neutrophils and B cells. This specificity allows IFN-lambda to play a pivotal role in mucosal immunity, particularly at barrier sites, such as the respiratory and gastrointestinal tracts. Emerging evidence suggests that IFN-lambda has a dual role in both enhancing antiviral immunity and regulating inflammation, thus offering a promising therapeutic strategy for diseases like systemic lupus erythematosus, rheumatoid arthritis, asthma and various cancers. However, the precise mechanisms by which IFN-lambda influence immune modulation and disease progression remain an area of active investigation. This review aims to provide an overview of the structure, function and signalling pathways of IFN-lambda, exploring their role in immune-related diseases and discussing potential avenues for therapeutic intervention.

关键词： helminth   parasite   Heligmosomoides   nematode   immunomodulation   IL-33   HpARI   HpBARI   vaccine  

摘要： The murine intestinal nematode Heligmosomoides polygyrus bakeri (Hpb) modulates the host immune response via the Hpb alarmin release inhibitor (HpARI) family (HpARI1/2/3), which acts on interleukin (IL)-33, and the Hpb binds alarmin receptor and inhibits (HpBARI) family (HpBARI and HpBARI_Hom2), which acts on the IL-33 receptor ST2. Here, we find that this immunomodulation is evident only in the first week of infection and affects local and distal tissues. Vaccination with HpARI or HpBARI proteins raises antibody responses that block their immunomodulatory activities: HpARI2 vaccination results in significantly increased type 2 innate lymphoid cells (ILC2s), T helper (Th)2, and serum IL-4 and IL-5 responses, while HpBARI + HpBARI_Hom2 vaccination reverses infection-mediated ST2 suppression and increases Th2 immunity. A cocktail of HpARI2 + HpBARI + HpBARI_Hom2 gives robust protection against infection, associated with stunting of adult parasites, reduced egg burden, increased type 2 immune responses, and intestinal goblet cell expansion. Therefore, vaccination with immunomodulatory proteins can protect the host against infection and can be used as a tool for blocking the effects of specific parasite-derived proteins.

摘要： Oligodendroglia expressing major histocompatibility complex (MHC) molecules have become of central interest in multiple sclerosis (MS) research, but their role in aging is still being elucidated. Using MHC class I and II reporter mice, we compared oligodendroglial MHC expression in neonatal, young adult (8-16 weeks), and aging (52 weeks) mice at baseline and after stereotactic delivery of AAV-GFAP-IFN gamma. We found that MHC class I-expressing oligodendroglia were present in both the na & iuml;ve brain and spinal cord, while MHC class II-expressing oligodendroglia were seen only in the spinal cord of aging mice at baseline. After AAV injection, MHC expression in oligodendroglia increased, recapitulating pathology seen in MS mouse models and in MS post-mortem tissue. After IFN gamma-AAV injection, the abundance of MHC class I-expressing oligodendroglia did not vary with age, whereas MHC class II-expressing oligodendroglia were more abundant in aging mice than neonatal and young adult mice. Our results suggest that MHC class II-expressing oligodendroglia are more prevalent with aging, which may contribute to the mechanisms underlying progressive MS and other age-related neurodegenerative diseases with central nervous system inflammation.

关键词： Natural killer (NK) cells   Cryopreservation   Good manufacturing practice (GMP)   Cell therapy   Immunotherapy   Advanced therapy medicinal product (ATMP)  

摘要： The adoptive transfer of natural killer (NK) cells represents a promising cancer therapy due to their intrinsic ability to distinguish between malignant and healthy cells in an allogeneic context, enabling off-the-shelf manufacturing possibilities. On demand availability of cryopreserved advanced therapy medicinal products (ATMPs) could promote enrolment in clinical trials and eventually commercialization with repeated dosing possibilities. However, NK cells are considered highly sensitive to cryopreservation-induced defects, including impaired viability, anti-tumor cytotoxicity, and in vivo expansion capacity. Here, we present the GMP-compliant manufacturing of an off-the-shelf NK cell product (RNK001), derived ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPCs). To facilitate scalability and reduce hands-on time, the production process was adapted to a G-rex bioreactor, yielding high numbers of a pure CD56+CD3- NK cell product. Cryopreservation of HSPC-NK cells using an optimized freeze-thaw protocol resulted in a consistently high post-thawing viability of mature and differentiated cells. Surviving HSPC-NK cells post-thawing exhibited enhanced proliferative capacity compared to fresh cells in vitro and their persistence in vivo was similar to that of fresh cells when administrated intravenously or intraperitoneally in NOD/SCID/IL2Rgnull mice. Moreover, cryopreserved HSPC-NK cells had robust anti-tumor functionality, efficiently killing tumor spheroids embedded in a 3D collagen matrix and maintaining degranulation and interferon-gamma production capacity comparable to fresh cells following in vivo infusion. Together, these findings show the potential of cryopreserved HSPC-NK cells with potent effector functions, allowing the manufacturing of an off-the-shelf therapeutical NK cell product for hematological and solid malignancies.

关键词： Brain tumor segmentation   Multimodal MRI   Mamba   Hadamard product  

摘要： Brain tumor segmentation from multimodal magnetic resonance imaging is essential for computer-aided diagnosis and therapy formulation. There are still a number of obstacles in the accurate segmentation for the computer-assisted application. CNN-based encoder faces challenges in capturing long-range dependencies and lacks robustness when using skip connections, which leads to loss of details and affects segmentation accuracy. Transformer-based encoder can obtain global context, but it is limited by computational constraints when processing high-resolution medical images. To address these issues, we propose MHC-SegNet, a novel Mamba-Hadamard collaboration segmentation network that aims to more efficiently capture global patterns across modalities. We design a collaboration encoder-decoder with scale-aware Mamba encoder and triple-axis group Hadamard product to capture long-range dependencies and extract multi-perspective 3D spatial features with computationally efficient. In addition, scale-aware feature refinement layers are also proposed to represent and aggregate multi-scale information in the collaboration encoder, and a hierarchical fusion skip module is designed to address the loss of detail caused by vanilla skip connections. The proposed modules enable the network to achieve a comprehensive understanding of the input data, and accurately identify tumor features. Experimental results demonstrate that our model achieves the best performance compared to recent state-of-the-art models in segmentation accuracy.

关键词： porcine teschovirus   3C(pro)   NF-kappa B   inhibitor   protease activity  

摘要： Porcine teschovirus (PTV) circulates in pig populations, causing clinical diseases such as poliomyelitis, reproductive disorders, and pneumonia. However, the molecular mechanisms underlying the pathogenesis of PTV infection have not been fully elucidated. Here, we found that PTV infection does not activate the promoters of NF-kappa B or IFN-beta. The expression of PTV 3C(pro) inhibits the promoter activity of NF-kappa B and IFN-beta stimulated by SeV and inhibits the downstream transcription of NF-kappa B and IFN-beta by blocking the phosphorylation and nuclear translocation of NF-kappa B. Coimmunoprecipiation (co-IP) experiments demonstrated that 3C(pro) and NF-kappa B interact. The degradation of NF-kappa B was unaffected by inhibitors targeting lysosomes (NH4Cl), proteasomes (MG132), or caspases (Z-VAD-FMK). The protease activity of 3C(pro), which relies on its catalytic active site, is vital for NF-kappa B cleavage and degradation. Loss of proteolytic activity in mutants abolished NF-kappa B degradation, impairing the ability of 3C(pro) to suppress SeV-induced innate immunity and restore VSV-GFP replication, thereby underscoring its critical role in immune evasion by targeting NF-kappa B. This study reveals novel mechanisms underlying PTV-mediated suppression of host innate immunity.

关键词： Diabetic foot (DF)   Circular RNAs   hsa-HLA-DRB1   miRNA_12118   FLT-1  

摘要： We investigated the role and mechanism of hsa-HLA-DRB1 in the development and progression of diabetic foot ulcers. High-throughput sequencing was performed on three normal foot trauma tissues and diabetic foot ulcer tissues. The circRNAs with significant differences were identified. The downstream miRNAs were predicted by miRanda and RNAhybrid databases, and the mRNAs were predicted by the TargetScan database. Validation was performed with CCK8, flow cytometry, trabecular scratch assay, tubule generation assay, Western blot, dual luciferase assay, and RT-qPCR. High-throughput sequencing identified 461 significantly different circRNAs, of which 260 were up-regulated and 201 down-regulated. Compared to normal tissue, hsa-HLA-DRB1 was highly expressed in diabetic foot ulcers. The hsa-HLA-DRB1/miRNA_12118/FLT-1 axis was constructed. In vitro, we found that HLA-DRB1 overexpression inhibited cell viability, wound healing, and tubule formation, promoted apoptosis, and enhanced FLT-1 expression in HUVECs. The upregulation of hsa-HLA-DRB1 may promote diabetic foot development The upregulation of hsa - HLA - DRB1 may inhibit the biological function of endothelial cells by targeting miRNA_12118 and acting on FLT - 1. by targeting miRNA_12118 and acting on FLT-1. Therefore, our study highlights the key role of the hsa-HLA-DRB1/miRNA_12118/FLT-1 axis in diabetic foot trauma.

关键词： IL-4   IL-13   IL-31   itch   type 2 inflammation   neuroimmune interactions   neuroarchitecture   sensory neurons   AD   Atopic dermatitis   ANOVA   Analysis of variance   ARG1   Arginase 1   BSA   Bovine serum albumin   cAMP   cyclic adenosine monophosphate   CREB   cAMP response element binding   DEG   Differentially expressed gene   DMEM   Dulbecco's modified Eagle medium   DRG   dorsal root ganglion   EASI   Eczema area severity index   GDNF   Glial cell-line derived neurotrophic factor   GSEA   Gene set enrichment analysis   IENFD   Intraepidermal nerve fibre density   IL   interleukin   IRS   Insulin receptor substrate   MBP   Major basic protein   MCP   Monocyte chemoattractant protein   MSP   Macrophage stimulating protein   NGF   Nerve growth factor   PBS   Phosphate buffered saline   PFA   Paraformaldehyde   PGP9.5   Protein gene product 9.5   PN   Prurigo nodularis   RHOGDI   Rho-GDP dissociation inhibitor   RON   Recepteur d'Origine Nantais (also known as Macrophage-stimulating protein receptor   SCORAD   SCOring Atopic Dermatitis   SEM   Standard error of the mean   SNARE   Soluble N-ethylmaleimide-sensitive factor attachment protein receptor   SOCS   Suppressor of cytokine signalling 1  

摘要： Background Anti-type 2 cytokine therapies represent promising interventions for chronic itch; however, their precise mechanisms in restoring nerve architecture and mitigating inflammation and pruritus remain incompletely understood. Objectives This study aimed to elucidate the mechanistic roles of IL-4, IL-13, and IL-31 in the pathophysiology of itch associated with type 2 inflammatory skin diseases. Methods The effect of IL-4, IL-13, and/or IL-31 on neurite outgrowth and/or transcriptomic changes were analyzed in human and mouse dorsal root ganglion (DRG) neuronal cultures. Mouse ear pinnae were processed for histologic, transcriptomic, and proteomic analyses 4 days after intradermal injection of IL-4, IL-13, and/or IL-31. To evaluate functional correlations with neuronal responses, mice were subcutaneously challenged with IL-4, IL-13, and/or IL-31, and scratching behavior was monitored. Association between IL-4/IL-13–IL-4Rα axis and severity of atopic dermatitis (AD) was evaluated through correlative analyses of human DRG transcriptomic changes and AD transcriptomic datasets (GSE130588 and BioMap consortium). Results IL-4 and IL-13 promote mouse and human DRG sensory neuron growth, with effects similar to or greater than IL-31. In mice, intradermal IL-4, IL-13, and IL-31 increased epidermal nerve growth; however, only IL-4 and IL-13 induced hyperplasia and immune cell recruitment. Multi-omic analyses revealed that IL-4 and IL-13 have a broader impact on neuroimmune interactions than IL-31. In a murine DRG neuron-eosinophil co-culture, IL-4Rα blockade reduced neurite growth. IL-13 and IL-31 elicited acute scratching, demonstrating their roles as direct pruritogens; IL-4 synergistically enhanced IL-13-induced itch, resulting in greater pruritic responses than IL-31. Additionally, a set of itch-associated genes upregulated by IL-4 and IL-13 and downregulated by dupilumab-mediated IL-4Rα blockade in human DRG neuronal cultures showed positive correlation with AD sever