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关键词： glutamate   mGluR5   Crassostrea gigas   hemocyte   IL-17 expression  

摘要： Metabotropic glutamate receptor 5 (mGluR5) is a critical regulator of immune responses within the neuroimmune system, influencing cytokine secretion and immune cell function. Although extensively studied in mammals, its role in regulating IL-17 in invertebrate immunity is poorly understood. This study examines CgmGluR5 expression and downstream signaling activation in Pacific oyster (Crassostrea gigas) hemocytes following glutamate (Glu) and Vibrio splendidus treatment. Glu treatment significantly induced the expression of CgmGluR5 and key signaling molecules, including PLC, DAG, IP3, Ca-2(+), and PKC, while enhancing mRNA levels of CgIL17-1, CgIL17-5, and CgCaspase3. Elevated Ca-2(+) content and CgIL17 expression in hemocytes were observed at 12 h post-Glu exposure, indicating CgmGluR5-mediated immune regulation through the phosphoinositide pathway. A 1.14-fold increase in the apoptosis rate was found in the Glu treatment group compared to the control group. Knockdown of CgmGluR5 suppressed CgIL17-1 and CgIL17-5 expression and reduced granulocyte proportions, reflecting its role in immune regulation. This study shows that CgmGluR5 mediates long-term immune regulation in oysters through the phosphoinositide pathway, providing new theoretical insights for aquaculture immune management.

摘要： Immune aplastic anemia (iAA) frequently results in transfusion dependence for platelets and packed red blood cells (PRBC), increasing the risk for complications. The most common immune mediated cause for platelet transfusion refractoriness is due to alloimmunization with human leukocyte antigen (HLA) antibody (Ab) to non-self class I antigens (Ag). The clinical impact of the HLA alloimmunization has not been well studied in patients with iAA. We investigated the clinical relevance of HLA alloimmunization in our large iAA patient cohort from 5 prospective trials, and its correlation with disease outcomes. Of 444 severe aplastic anemia (SAA) patients treated with immunosuppressive therapy (IST), 99 (22%) had HLA alloimmunization. Presence of HLA Ab was associated with shorter overall survival (OS), reduced responses to immunosuppressive therapy (IST) and higher risk of clonal evolution. Our data suggest that HLA alloimmunization is a marker of disease outcome. Furthermore, using single cell RNA sequencing, we show enhanced activation of both complement mediated pathways and the adaptive immune system in alloimmunized patients, indicating an interconnection between immune compartments.

关键词： donor-specific HLA antibodies   pneumococcal vaccine   zoster vaccine   renal transplant   vaccination in kidney transplant   vaccines induced HLA antibodies  

摘要： Background In renal transplant waitlisted patients, vaccinations remain the standard of care for infection prevention. The vaccine and its adjuvant sensitizer can be potential sources for the induction of donor-specific antibodies (DSA) against human leukocyte antigens (HLA). These novel HLA antibodies can result in a positive flow cell crossmatch (FCXM), which can make a previously compatible live donor *** report We present an adult renal transplant waitlisted patient who has had multiple negative T-cell and B-cell FCXM with no detection of DSA at baseline. The patient then received a single dose of pneumococcal conjugate (PCV13) and a second dose of recombinant zoster vaccine (RZV). After these vaccinations, the patient's FCXM was positive for both T-cells and B-cells and the HLA class I antibodies (A1, 23, 24, 80;B44, 45, 76) showed a calculated panel reactive antibody (cPRA) of 51%. A1 and B44 DSA were detected which predicted incompatibility with the patient's planned live donor renal transplant. The patient had to enter the kidney-paired donation program instead and receive their transplantation after 16 *** RZV or PCV13 vaccines or their adjuvant components can potentially cause allosensitization in renal transplant waitlisted patients. The detection of DSA can result in reduced access to compatible transplants. With advances in HLA immunogenetics, better tools can monitor HLA-specific memory B-cells to provide crucial insights into the primary mechanism of action of HLA DSA antibody formation and suggest interventions to mitigate this memory B-cell activation.

关键词： Anti-TNF therapy   Autoinflammation   Innate immune cells   Systemic autoinflammatory diseases   TNF inhibitors: TNFR1   TNFR2  

摘要： Systemic autoinflammatory diseases (SAIDs) are rare conditions resulting from innate immune system dysregulation, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most SAIDs are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor (TNF) is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-TNF therapy is widely used in the clinical management of SAIDs. TNF inhibitors block the interaction of TNF with its two receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). These inhibitors primarily target soluble TNF (sTNF), which mainly binds to TNFR1, exerting anti-inflammatory effects. Interestingly, TNF inhibitors also affect transmembrane TNF (tmTNF), which engages TNFR2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. TNF inhibitors also promote the release of soluble TNFR2 (sTNFR2), which neutralizes circulating TNF. Some agents targeting TNFR2 can even act as agonists, triggering reverse signaling by binding to tmTNF. While effective, prolonged use of TNF inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of TNF receptors. More thoroughly understanding of the mechanisms underlying the action of TNF inhibitors is required to develop more effective and safer treatment for SAIDs. This article reviews current studies on the role of the innate immune system in SAID pathogenesis, the impact of anti-TNF therapy on innate immune cells, and perspectives on developing improved agents targeting TNF or its receptors.

关键词： Dendropanax morbiferus   reactive oxygen species   tumor necrosis factor-alpha   matrix metalloproteinase-1   MAPKs pathway   human dermal fibroblast  

摘要： In this study, we investigated the antiaging potential of dendropanoxide (DP), an active compound derived from Dendropanax morbiferus, in human dermal fibroblasts (NHDFs) induced by Tumor Necrosis Factor-alpha (TNF-alpha) and in human epidermal keratinocytes (NHEKs) induced by TNF-alpha and interferon gamma (IFN-gamma). We induced oxidative stress related to ultraviolet (UV) radiation with TNF-alpha and IFN-gamma and then treated the cells with various concentrations of DP to evaluate its effects on reactive oxygen species (ROS) production, matrix metalloproteinase-1 (MMP-1) expression, collagen synthesis, inflammatory cytokine expression, and skin barrier protection. The results showed that DP significantly reduced ROS production, indicating its potential to alleviate oxidative stress in the skin. Additionally, DP effectively inhibited MMP-1 production, suggesting that it could prevent collagen degradation in the dermis, significantly increase the secretion of pro-collagen I, promote collagen synthesis, and protect the dermal extracellular matrix (ECM). Moreover, DP significantly reduced the expression of inflammatory cytokines IL-1 beta and IL-6, thereby inhibiting excessive inflammatory responses in the skin. DP also enhanced the gene expression of key factors involved in skin barrier maintenance, including Kazal-type 5 (SPINK5), loricrin (LOR), aquaporin-3 (AQP3), filaggrin (FLG), and keratin 1 (KRT1), suggesting its potential to maintain and protect the skin barrier. Western blot analysis revealed that DP inhibited TNF-alpha-induced phosphorylation of JNK and p38, implying that DP exerts antiaging effects through the regulation of the JNK and p38 signaling pathways. Collectively, these findings suggest that DP has significant potential as an antiaging agent.

关键词： HLA-E   NKG2A/CD94   T cell receptor   peptide/receptor interactions  

摘要： The virtually monomorphic antigen presentation molecule HLA-E can present self- and non-self peptides to the NKG2A/CD94 co-receptor inhibitory complex expressed on natural killer (NK) cells and to T cell receptors (TCRs) expressed on T cells. HLA-E presents self-peptides to NKG2A/CD94 to regulate tissue homeostasis, whereas HLA-E restricted T cells mediate regulatory and cytotoxic responses toward pathogen-infected cells. In this study, we directly compared HLA-E/peptide recognition and signaling between NKG2A/CD94 and 2 HLA-E restricted TCRs that can recognize self-peptides or identical peptide mimics from the viral UL40 protein of cytomegalovirus using position substituted peptide variants. We show that position 7 is critical for interaction with NKG2A/CD94, whereas position 8 is important for interaction with the TCRs. The Arginine at position 5 of these peptides is an essential residue for recognition by both receptors. Thus, NKG2A/CD94 and TCRs have different requirements for recognition of peptides presented in HLA-E.

关键词： Dictamnus dasycarpus turcz.   Chemical composition   Rheumatoid arthritis   Alkaloid  

摘要： Ethnopharmacological relevance: Rheumatoid Arthritis (RA), a chronic inflammatory autoimmune condition, presents a substantial challenge to public health. Dictamnus dasycarpus Turcz. (D. dasycarpus) is a traditional Chinese medicinal plant recognized for its anti-inflammatory properties and is increasingly being utilized as a potential anti-RA agent, but the underlying mechanism is still unclear. Aim of the study: The objective of this research is to elucidate the potential active components and therapeutic properties of D. dasycarpus in experimental RA-induced DBA/1J mice, and to uncover the pharmacological basis of its action. Materials and methods: Surface plasmon resonance (SPR) was employed to ascertain the specificity of interactions between protein targets and D. dasycarpus active ingredients for treating RA. The extract of D. dasycarpus was obtained by HP-20 microresin column chromatography, and its chemical composition was assessed using UPLCOrbitrap-MS. This study utilized a collagen-induced arthritis (CIA) mouse model for in vivo experimentation. Body weight, foot thickness measurements, arthritis scores, immune organ index, and serum antibody levels of mice were used as indicators to evaluate the effects of D. dasycarpus components in treating RA. The serum levels of inflammatory factors in mice were measured using a cytokine antibody microarray assay. Additionally, this study quantified the protein expression levels associated with inflammatory responses through a combination of immunohistochemical staining and western blotting analyses. Results: This research investigated the interaction between D. dasycarpus active components and target proteins, including PTPN14, using a BIACORE system. The screened active components were identified as alkaloids through mass spectrometry. The UPLC-Orbitrap-MS analysis revealed that alkaloids were the predominant constituents in the 60% EtOH extract of D. dasycarpus. Alkaloid components significantly reduced the arthr

关键词： Infectious disease and host defense   Innate immunity and inflammation   Mucosal immunology  

摘要： To distinguish pathogens from commensals, the intestinal epithelium employs cytosolic innate immune sensors. Activation of the NAIP-NLRC4 inflammasome initiates extrusion of infected intestinal epithelial cells (IEC) upon cytosolic bacterial sensing. We previously reported that activation of the inflammasome in tuft cells, which are primarily known for their role in parasitic infections, leads to the release of prostaglandin D2 (PGD2). We observe that NAIP-NLRC4 inflammasome activation in tuft cells leads to an antibacterial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD2 signaling. A NKp46+ subset of ILC3 expresses the PGD2 receptor CRTH2 and is the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium in the distal small intestine. However, tuft cells in the cecum and colon are dispensable for antibacterial immunity. These data support that intestinal tuft cells can also induce antibacterial responses, possibly in a tissue-specific manner.

关键词： pulmonary function   Tephrosia purpurea   pseudosemiglabrin   iNOS   pancreas   ischemia   reperfusion  

摘要： Ischemia-reperfusion (IR) injury is a major cause of multiple organ failure. The purpose of this study was to look into the role of Tephrosia purpurea (TEP) and its active constituent pseudosemiglabrin (PS) in alleviating severe acute pancreatitis and its associated acute lung injury. We established a rat pancreatic IR model, and the rats were treated with TEP (200 mg/kg and 400 mg/kg) and PS (20 and 40 mg/kg), in addition to the IR control and sham groups. The results showed that the respiratory parameters, including inspiratory time (Ti), expiratory time (Te), duration (Dr), and respiratory rate (RR), were comparable among all groups, while peak inspiratory flow (PIF), forced vital capacity (FVC), and forced expiratory volume at 0.1 s (FEV0.1) were significantly impaired. Notably, PS at 40 mg/kg showed normal PIF, FVC, and FEV0.1/FVC compared to the IR group, indicating an improved lung function. Additionally, TEP and PS showed protective effects on pancreatic and lung tissues compared to the IR control group, with the following effects: alleviating pathological damage;reducing serum levels of trypsinogen activation peptide (TAP), lipase, and amylase;decreasing oxidative stress markers such as MDA and MPO;restoring antioxidant enzyme activity (GPx);suppressing inflammatory markers TNF-alpha, IL-6, and NF-kappa B;downregulating HMGB1 gene in pancreatic tissue;and upregulating the IL-22 gene in lung tissues. In conclusion, the obtained findings demonstrate that oral supplementation of TEP and PS to rats with pancreatic IR alleviates pancreatic and lung injuries by reducing oxidative stress and modulating inflammatory processes, which offers an attractive therapeutic option for severe acute pancreatitis and its associated acute lung injury.

关键词： Fengshi gutong capsule   Rheumatoid arthritis   TNF-alpha   Bone destruction   Inflammation  

摘要： Ethnopharmacological relevance: Fengshi Gutong Capsule (FSGT) is a proprietary Chinese medicine with established clinical efficacy in Rheumatoid arthritis (RA);however, its underlying mechanisms remain unclear. Aim: This study aims to elucidate the mechanisms by which FSGT alleviates RA. Materials and methods: A collagen-induced arthritis (CIA) rat model was employed to assess the therapeutic effects of FSGT in RA. Network pharmacology and proteomics were integrated to identify potential mechanism and molecular targets, which were further validated via Western blot analysis. Molecular docking and microscale thermophoresis (MST) were utilized to assess the binding affinities of FSGT's active components to key proteins. Results: FSGT (280 and 840 mg/kg) alleviated CIA-induced RA in rats without significant side effects. Network pharmacology and label-free proteomic analysis displayed that FSGT exerted its therapeutic effects by modulating inflammation and bone destruction. FSGT significantly reduced serum levels of inflammatory cytokines and their protein expression in the ankle joints and synovial tissues. Additionally, FSGT attenuated bone destruction and significantly reversed the expression of bone destruction-related proteins. Molecular docking revealed that 18 active compounds in FSGT exhibited strong binding affinity for TNF-alpha, with hypaconitine, 18 alpha glycyrrhizic acid, and naringenin further validated by MST assays. Conclusion: FSGT improved CIA-induced RA in rats by targeting TNF-alpha to reduce inflammation and inhibit bone destruction, offering insights into its therapeutic mechanisms in RA.