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关键词： biofilm-infected diabetic ulcers   core-shell microneedle   macrophage polarization   spatiotemporal immunomodulatory  

摘要： Macrophage phenotypic dysregulation, spatially by biofilm and dynamically in time, impedes the healing of diabetic ulcers (DUs). Effective treatment requires enabling spatiotemporal regulation of macrophage polarization, balancing the M1 pro-inflammatory antimicrobial response with the M2 anti-inflammatory tissue-regeneration response. Here, a core-shell microneedle system (LM-MG@MN) is proposed with spatiotemporal immunomodulation features, designed to spatially disrupt biofilm barriers and sequentially induce macrophage polarization from M0 to M1 and subsequently to M2 by regulating the NLRP3/IL-1 beta pathway. Glucose oxidase (GOX)-loaded 2D MXene nanosheets (MG) are encapsulated in a hyaluronic acid-beta-cyclodextrin (HA-beta-CD) matrix as the MN shell layer. The rapid dissolution of this shell triggers MG to induce pro-inflammatory polarization of macrophages from M0 to M1, aiding in clearing biofilm infections. Liposomes (LM) carrying the NLRP3 inflammasome inhibitor MCC950 are embedded within a methacrylate hyaluronic acid (HAMA) matrix in the MN core. In the later stages of wound healing, LM is released gradually from the core, promoting the anti-inflammatory polarization of macrophages from M1 to M2 and accelerating tissue regeneration by enhancing crosstalk with fibroblasts and endothelial cells. Additionally, RNA sequencing indicates that LM-MG@MN regulates macrophage metabolic reprogramming to enhance DUs healing. This spatiotemporal immunomodulation strategy offers a promising approach for clinical DUs treatment.

关键词： HSCT   Chimerism   HLA   CMV   GvHD  

摘要： Several studies have investigated the association between HLA alleles and cytomegalovirus (CMV) infection following hematopoietic stem cell transplantation (HSCT). It was found that many HLA alleles were associated with increased rate of CMV infection, while others had a protective effect against infection. However, to our knowledge no studies have investigated the effect of this relation on chimerism status post transplantation. Previous results concluded that CMV reactivation or infection increases conversion from mixed chimerism toward complete chimerism (CC) as a consequence of concomitant activation of immune system. Our aim is to study the association of CMV and certain HLA alleles and their effect on chimerism status post transplantation and identify other factors affecting chimerism status. 165 patients who underwent allogeneic HSCT for different hematological indications were studied. Both recipients (R) and donors (D) underwent serological testing for CMV-specific IgG and IgM, HLA typing, and chimerism analysis. CMV infection or reactivation was assessed in recipients through weekly monitoring of CMV DNA. Patients were followed up for 100 days where chimerism analysis was performed at 28, 60, 90, and 100 days post-transplantation. Eighty-five patients were positive for CMV by PCR post transplantation while eighty patients were CMV negative. Acute graft versus host disease (aGvHD) was significantly increased in CMV positive patients. Multivariate analysis (MVA) has indicated that HLA-A*2, HLA-B*14, HLA-B*41, HLA-DRB1*04 and HLA-DRB1*13, as well as a diagnosis of myelodysplastic syndrome and bone marrow aplasia, significantly increased the risk for CMV positivity post transplantation. HLA-DRB1*11 positivity was associated with a higher rate of aGvHD. CMV infection/reactivation as indicated by positive CMV PCR post-transplant was associated with a faster rate of conversion toward CC, and this effect was independent of the implemented conditioning regimen or t

关键词： inflammatory bowel disease   interleukin 17   interleukin 23   nociception   PI3K   TRPV1   visceral pain  

摘要： Managing visceral pain associated with gastrointestinal (GI) disease remains a significant challenge due to the gut-related side effects and contraindicated use of many commonly used painkillers in people with inflammatory bowel disease (IBD). Consequently, it is crucial to deepen our understanding of the mediators and mechanisms underlying inflammatory pain in people with IBD. To do this, we compared bulk RNA sequencing data from colonic biopsy samples from people with IBD with single-cell RNA sequencing data from colon-projecting dorsal root ganglion (DRG) neurons in mice to generate an interactome of putative pro-nociceptive cytokine signalling pathways. This in silico analysis revealed a 10-fold increase in IL17A expression in samples from people with ulcerative colitis (UC) alongside marked co-expression of Il17ra with Trpv1 in colon-projecting DRG neurons in mice, highlighting a likely role for interleukin-17 (IL-17) in colonic nociceptor signalling in people with UC. In support of this, Ca2+ imaging studies demonstrated that IL-17 stimulates DRG sensory neurons co-sensitive to capsaicin in male and female mice, with a similar proportion responding in neuron-enriched cultures generated by magnetic-activated cell sorting, thus confirming that IL-17 directly activates DRG neurons. IL-17-evoked Ca2+ signals were attenuated by TRPV1 inhibition, consistent with nociceptor activation, and blocked by inhibition of phosphoinositide 3-kinase (PI3K) activity, consistent with the known role for PI3K as a downstream effector of IL-17 receptor signalling. In keeping with these observations, IL-17 enhanced colonic afferent responses to colorectal distension at noxious distension pressures in male mice, an effect also blocked by PI3K inhibition. Overall, these findings demonstrate a pro-nociceptive effect of IL-17 in the GI tract, thus highlighting the potential utility of IL-17-targeting therapies to reduce pain in people with ***

关键词： Doxorubicin   Interleukin-17A   Secukinumab   Nuclear factor kappa beta   Pyrin domain containing 3   Interleukin-1 beta  

摘要： Doxorubicin (DOX) is used as a chemotherapeutic drug for treating cancer. Nevertheless, it causes damage to the heart by activating inflammatory pathways, resulting in cardiotoxicity. Imbalance in cytokine production is a crucial component that might trigger the initiation of inflammatory processes. Inflammatory cytokines could be targeted therapies against cardiovascular diseases (CVDs). Interleukin-17A (IL-17A) is a cytokine that promotes inflammation and stimulates harmful immunological reactions. The objective of the study was to determine the efficacy of secukinumab (SEC), a completely human monoclonal IgG1/kappa antibody that targets IL-17A, in ameliorating DOX-induced cardiotoxicity (DIC). We administered 2.5 mg/kg of DOX intraperitoneally to male Wistar rats three times a week for 2 weeks and simultaneously administered 0.9 mg/kg of SEC along with 2.5 mg/kg of DOX injection three times a week for a duration of two weeks. The findings indicated that DOX induced damage to the heart tissue, resulting in a significant rise in indicators of cardiotoxicity (P < 0.001), as well as oxidative stress and inflammation. DIC may have arisen from DOX's activation of the Pyrin domain containing 3 (NLRP3) inflammasome and the nuclear factor kappa beta (NF-kappa B) pathway. The co-administration of SEC successfully reversed all DOX-induced abnormalities by restoring cardiac functions to their baseline levels, decreasing levels of inflammatory mediators such as IL-17A and interleukin-1 beta (IL-1 beta), and improving oxidative stress by reducing levels of malondialdehyde (MDA) and increasing levels of reduced glutathione (GSH). Furthermore, it mitigated the heightened activation of the NF-kappa B/NLRP3 pathway caused by DOX. This study shows that IL-17A neutralization can prevent DIC by regulating the NF-kappa B/NLRP3/Caspase-1/IL-1 beta pathway to be used as potential therapeutic target for CVDs.

关键词： Mast cells   Psoriasis   IL-17   RORC  

摘要： Background: The proinflammatory cytokine IL-17 is known to play an important role in psoriasis pathogenesis, but little is known about its regulation in psoriasis or after treatment. Objective: Aiming to investigate the role of IL-17 regulation in the resolution of psoriasis, we analyzed biopsy samples from patients with plaque psoriasis, including non-lesional and lesional skin at baseline and after anti-IL-17 and -IL-23 antibody, topical dithranol or UVB treatment as well as skin from healthy donors. Methods: Skin biopsy samples were analyzed using immunostaining, RNA sequencing and in situ mRNA detection. In addition, we investigated IL-17 concentration of primary human skin mast cell supernatants after stimulation with the pro-inflammatory cytokines TNF alpha, IL-22, IL-23 and IFN gamma. Results: A high number of IL-17A+ mast cells persisted in resolved lesions after treatment and correlated inversely with the time span in remission. IL-17A+ mast cells were found in T cell-rich areas and near resident memory T cells in active and resolved lesions. CIBERSORTx deconvolution of RNA-seq data of active and dithranol-treated psoriasis lesions showed that activated mast cells were increased in psoriatic skin but returned to normal levels after treatment. Primary skin mast cells responded with an increased release of IL-17A after stimulation with the pro-inflammatory cytokines and in situ mRNA detection revealed positive signals for IL17A, IL17F and RORC in mast cells. Conclusion: Thus, together with T cells, mast cells seem to be important players of the IL-23/IL17 axis underlying psoriasis pathogenesis and relevant for early disease recurrence. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology. This is an open access article under the CC BY license (http://***/licenses/

关键词： Arthrospira platensis   Pseudorabies virus   LncRNA  

摘要： Pseudorabies virus (PRV) poses a great danger to pig farming and human public health safety. Previous studies have shown that the first component of Arthrospira platensis polysaccharide (PAP-1) may alleviate the inflammatory response of RAW264.7 cells induced by PRV infection through the IL-17RA signaling pathway and its circRNA-miRNA-mRNA network, but the specific mechanism is not clear. In this study, we screened the LncRNA sequences related to IL-17RA signaling pathway by transcriptomics data. The mechanism was verified by gene interference or overexpression and dual luciferase experiments to investigate the regulatory mechanism of PAP-1 on IL-17RA inflammatory signaling pathway in PRV infection. In vitro studies showed that PAP-1 significantly reduced the PRV-induced elevated expression of IL-17RA signaling pathway inflammatory factors such as IL-17RA, IL-1 beta, CXCL10, and iNOS in RAW264.7 cells (P < 0.05). On this basis, the key regulatory factor LncRNA Dhx35 of IL-17 RA signaling pathway was screened by whole transcriptome sequencing analysis. It was found that PAP-1 could reduce the transcriptional activity of IL-17RA by down-regulating PRV-induced LncRNA Dhx35 as a competing endogenous RNA to bind to mmu-miR-185-3p, which decreased the inflammatory response. In vivo experiments revealed that PAP-1 down-regulated the expression of LncRNA Dhx35, up-regulated the expression of mmu-miR-185-3p, and significantly down-regulated the expression of IL-17RA, IL-1 beta, CXCL10, and iNOS in lung tissues of PRV-infected mice (P < 0.05). Taken together, our data suggest that PAP-1 reduces PRV infection-induced inflammatory responses in RAW264.7 cells and mouse lung tissues by regulating LncRNA Dhx35/mmu-miR-185-3p/IL-17RA.

关键词： Trained immunity   Neutrophils   Bactericidal activity   Turbot  

摘要： Trained immunity refers to the immune memory of innate immune cells, which is driven by metabolic rewiring and epigenetic reprogramming after initial stimulation. Several endogenous inducers of trained immunity have been reported, such as oxidized low-density lipoprotein (oxLDL), interleukin, and interferon. However, the negative regulatory molecules of trained immunity remain largely elusive. In this study, we identify a member of IL-1 family receptors, interleukin-1 receptor 2 (IL-1R2), as a potential inhibitory regulator of trained immunity in turbot. Pre-incubating recombinant IL-1R2 protein (rIL-1R2) with turbot neutrophils could inhibit (3-glucaninduced training phenotypes. Specifically, rIL-1R2 incubation significantly decreases the expression of genes involved in the TLR/IL-1R and downstream MAPK/NF-kappa B signaling pathway in trained neutrophils, and further reversing the elevated expression of pro-inflammatory cytokines such as IL-6 and TNF-alpha in response to bacterial reinfection. Moreover, rIL-1R2 inhibits the increasing production of intracellular reactive oxygen (ROS), myeloperoxidase (MPO) activity and neutrophil extracellular traps (NETs) in trained neutrophils, ultimately impairing the bacterial killing ability. Taken together, our work demonstrates that the decoy receptor IL-1R2 could negatively regulate trained immunity activation in turbot neutrophils. These findings enrich the theory of trained immunity in teleost fish and provide a potential target for disease prevention and treatment in aquaculture.