Immunological Investigations最新文献

Background: Ulcerative Colitis (UC) is a condition that causes ulceration and inflammation of the intestinal epithelium. UC treatment depends on macrophages' phenotypic switch from pro-inflammatory (M1) to anti-inflammatory and tissue-repairing (M2). It has been reported that the epigenetic alteration of histone lactylation affects macrophage activity and phenotype. TAK-242, a TLR4 inhibitor, stimulates histone lactylation to generate reparative M2 UC macrophages.

Methods: This review highlighted the significance in terms of introduction, an overview of histone lactylation, the mechanism of action of TAK-242 in regulating inflammatory responses, the relationship between TAK-242 to histone lactylation, the potential role of TAK-242-dependent histone lactylation in macrophage polarization, the role of repair macrophages in ulcerative colitis and regulation of repair macrophages by histone lactylation.

Results: Novel treatments for ulcerative colitis involve the use of TAK-242 to enhance histone lactylation, which in turn boosts macrophage function and promotes mucosal healing.

Conclusion: TAK-242 exhibits therapeutic potential in the treatment of UC, and this research suggests further investigation and clinical trials to enhance patient outcomes.

Background: Carotid arteriosclerosis is common, with interventional therapy being the primary treatment. However, postoperative restenosis and poor stent patency, related to vascular inflammation involving MAPK and PP2A, limit success. Formononetin (FOR) may offer a novel approach by activating PP2A and inhibiting MAPK, reducing inflammation and improving outcomes.

Methods: Rats were divided into sham and carotid artery balloon injury (CABI) groups, with the latter receiving various concentrations of FOR. Vascular damage and inflammation were assessed using HE staining, ELISA, Western blot, and immunohistochemistry. HUVECs were treated with Ox-LDL to induce injury, followed by FOR (10-40 μM) and the MAPK inhibitor U0126. PP2A and MAPK expression were analyzed via Western blot and immunofluorescence.   .

Results: HE staining showed carotid lumen narrowing and tissue damage in the model group, which improved with FOR treatment. ELISA revealed reduced IL-6 and TNF-α levels post-CABI with FOR. FOR also reversed the decrease of PP2A and increased MAPK expression, along with reduced ERK1/2 phosphorylation. Conclusion FOR reduces vascular damage and inflammation after CABI via the PP2A/MAPK axis, enhancing vascular remodeling and restoring protein expression. FOR shows promise as a therapeutic agent for vascular injuries.

Conclusion: FOR can effectively reduce vascular damage and inflammation after coronary artery bypass grafting through the PP2A/MAPK axis, enhance vascular remodeling, and restore protein expression profiles. These findings suggest FOR as a promising therapeutic agent for vascular injuries.

Objective: To review the current and the potential research and clinical use of VLRBs.

Methods: A literature search was conducted for English studies published in the past 20 years using the terms "Variable Lymphocyte Receptor," "VLR," "VLRB" or "Repebody." Only primary reports were included.

Results: VLRB-based technologies are currently being investigated for diagnosis, imaging, and treatment of diverse conditions including solid organ and hematological malignancies, infectious diseases, autoimmunity, and degenerative and metabolic disorders. VLRB mAbs can be used to directly recognize disease biomarkers, such as B cells from chronic lymphocytic leukemia, or to deliver drugs to the brain or cancer cells. The VLRB C-terminal multimerization domain has been utilized to create vaccines while VLR-based chimeric antigen receptor (CAR) T cell constructs are being investigated for cancer therapies.

Conclusions: The extensive knowledge gained with VLRB mAbs in diverse in vitro and in vivo models emphasizes their promise for translation into clinical applications and readiness for prime time.

Background: The discovery of interleukin-2 (IL-2) and its receptor (IL-2R) almost 50 years ago revolutionized immunology, marking a pivotal moment in understanding T cell biology and immune regulation. Initially identified as a T cell growth factor, IL-2 unveiled critical insights into cytokine-mediated immune cell proliferation and differentiation.

Methods: This review highlighted the characterization of IL-2R as a multi-chain receptor complex set a precedent for decoding cytokine receptor signaling. The unique interplay between IL-2 and its high-affinity receptor component, IL-2Rα, epitomizes the principle of specificity and efficiency in cytokine signaling, enabling precise immune modulation. Regulatory T cells (Tregs) exploit IL-2Rα high affinity to outcompete effector T cells for IL-2, ensuring immune tolerance and preventing autoimmunity.

Results: Despite its foundational role in immune homeostasis, leveraging IL-2 for therapeutic purposes has proven challenging.

Conclusion: IL-2-based therapies hold transformative potential in autoimmunity, cancer immunology, and transplantation, yet they remain elusive due to the complex balance between immunostimulatory and immunosuppressive effects. This review explores the milestones in IL-2 biology, its dualistic functions, and the ongoing quest to harness its therapeutic promise.

Background: Interleukin-1 receptor 2 (IL1R2) and C-C motif chemokine receptor 2 (CCR2) as critical mediators of immune modulation and inflammation. This study aims to evaluate their functions in dextran sulfate sodium (DSS)-induced intestinal injury.

Methods: A DSS-induced intestinal injury model was established in C57BL/6 mice. Pharmacological inhibitors targeting IL1R2 or CCR2 were administered. Adipose-derived mesenchymal stem cell (ADMSC)-derived exosomes were isolated and loaded with IL1R2-siRNA, which were then administered to intestinal epithelial cells (IEC-6) or DSS-challenged mice.

Results: IL1R2 and CCR2 were upregulated in DSS-treated colon tissues. Pharmacological inhibition of IL1R2 or CCR2 improved body weight, restored colon length, reduced serum TNF-α and IL-6 levels, and preserved epithelial integrity in mice. miR-128-3p enriched in ADMSC-derived exosomes significantly reduced CCR2 expression in IEC-6 cells. Further loading of an IL1R2 siRNA in these exosomes led to a simultaneous inhibition of IL1R2. These exosomes reduced lipopolysaccharide-induced apoptosis and inflammation in IEC-6 cells and improved histological outcomes in DSS-challenged mice.

Conclusion: IL1R2 and CCR2 are key mediators of inflammation in DSS-induced intestinal injury. Dual inhibition of IL1R2 and CCR2 holds great promise for alleviating inflammatory responses and improving histological presentations in inflammatory bowel disease.

Background: MiR-519d-3p, also called specific placenta biomarkers, is a member of the Chromosome 19 miRNA Cluster (C19MC) with the highest concentrations of miRNAs in human placenta and maternal serum. These miRNAs are secreted by fetal trophoblast cells within extracellular vesicles (EVs) and interact with the mother's immune cells, which has been proposed to be crucial for immunological tolerance at the placental-maternal interface. A key mechanism in preeclampsia, a multifactorial, multipath hypertensive pregnancy illness, is an immunological imbalance between the mother and the fetus.

Methods: Using Next Generation Sequencing, we determined that the placenta-derived Exosomes (pEXOs) of preeclamptic patients had elevated expression of miR-519. To further develop an in vitro model of trophoblast-immune cell communication, HTR-8/Svneo cells and Jurkat T cells were employed and we utilized experiments such as Western blot (WB), Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR), Cell-Counting-Kit-8 (CCK-8) cell proliferation analysis, cell apoptosis analysis, and other techniques to accomplish research.

Results: It was discovered that miR-519d-3p in pEXOs promoted Jurkat T cell proliferation, inhibited apoptosis, and induced Jurkat T cell differentiation toward Th17.

Conclusion: MiR-519d-3p in pEXOs disrupts immune tolerance at the maternal-placental interface by encouraging Jurkat T cell proliferation, preventing Jurkat T cell apoptosis, and creating an imbalance in Th17/Treg differentiation. This likely leads to SIRS and unfavorable pregnancy complications like preeclampsia.

Introduction: T helper 17 (Th17) cells have a significant effect in the pathogenesis of asthma, and signal transducer and activator of transcription 3 (STAT3) pathway activation is critical for Th17 cell differentiation. Timosaponin A-III (TA3) was reported to inhibit the STAT3 pathway. Here, we investigated whether TA3 improved asthma by inhibiting the STAT3 pathway.

Methods:  Ovalbumin (OVA)-induced asthma murine models were developed, and TA3 (10 or 20 mg/kg) was gavage daily during OVA challenge. Murine naïve CD4⁺T cells were   triggered for Th17 differentiation, and TA3 (5 or 10 μM) was used to treat cells during induction of Th17 differentiation.

Results: In vivo experiments showed that TA3 decreased airway inflammation, goblet cell and smooth muscle hyperplasia, α-smooth muscle actin and collagen deposition, Th17 differentiation, and STAT3/RORγt signaling activation in mice exposed to OVA. The inhibitory effect of TA3 on STAT3/RORγt signaling activation was also observed in in vitro experiments. Compared to positive control static (a specific inhibitor of STAT3), TA3 had a similar effect on Th17 differentiation.

Discussion: These findings indicate that TA3 may ameliorate Th17 cell differentiation by suppressing STAT3/RORγt signaling. Our data provide evidence of the potential benefits of TA3 for the treatment of asthma.

Introduction: Hirsutella sinensis fungus (HSF)is an artificial substitute for Cordyceps sinensis and has shown promising therapeutic effects in various diseases including cancer. Previous studies have demonstrated that HSF can affect macrophage polarization and activate systemic immune response. In our preliminary experiments, we validated that HSF inhibited the proliferation of lung cancer (LC) cells, but the underlying mechanism is elusive. We intended to explore the mechanism of HSF in promoting anti-tumor immunity.

Methods: In vivo experiments were performed to confirm inhibitory effect of HSF on LC growth, and sequencing results revealed abnormal expression of CCRL2. Knockdown and overexpression of CCRL2 were conducted to investigate its effect on macrophage polarization, and co-culture with T cells was to assay the impact of HSF+CCRL2 on CD8⁺ T cell activation by flow cytometry.

Results: Overexpression of CCRL2 promoted macrophage polarization toward M1 and activated the proliferation and effector function of CD8⁺ T cells. HSF promoted CCRL2 expression and affected M1 polarization via CCRL2, which in turn affected CD8⁺ T cell-mediated anti-tumor immunity.

Discussion: Our study demonstrated that HSF promoted macrophage M1 polarization and activated CD8⁺ T cells via CCRL2, thereby inhibiting the progression of LC.

Background: Psoriasis (Pso) is a chronic, immune-mediated dermatological condition characterized by dysregulated inflammatory responses and the hyperproliferation of keratinocytes. Biologics, which target specific cytokines such as IL-17 and IL-23, have revolutionized the management by addressing key drivers of its pathophysiology. Despite their efficacy, biologics are not without limitations, including the need for intermittent administration and ongoing monitoring. In contrast, small molecules offer a promising alternative by selectively inhibiting key signaling pathways that modulate pro-inflammatory cytokines involved in the inflammatory cascade.

Methods and results: This review suggests a new therapeutic strategy for Pso treatment, emphasizing the intricate relationships between small molecules and important signaling pathways involved in the pathophysiology of skin conditions. Improving treatment outcomes and reducing the side effects associated with conventional medicines, this review aims to better understand how tailored small-molecule inhibitors might efficiently control these pathways. This creative approach promotes the creation of individualized treatment plans that can greatly enhance the quality of life of patients with Psoby utilizing the knowledge gathered from recent developments in signaling pathway research.

Conclusion: This review delves into the molecular mechanisms underlying Pso and explores how small molecules can be harnessed to enhance treatment outcomes, presenting a new paradigm for managing this chronic skin disorder.

Objective: This study investigated the mechanism of baicalin (BIA) attenuating the inflammatory response and lung injury in mycoplasma pneumoniae pneumonia (MPP) mice.

Methods: MPP mouse models were established and then treated with BIA, azithromycin, or NLRP3 inflammasome activator. Lung wet-to-dry weight (W/D) ratio were weighed. Serum levels of MP-IgM, C-reactive protein (CRP) and bronchoalveolar lavage fluid (BALF) protein were detected by kits, NLRP3/Caspase-1 pathway-related protein levels by Western blot, and IL-1β, IL-18, IL-6 and TNF-α levels by ELISA. HE staining was performed to detect lung injury.

Results: MPP mice showed elevated mouse lung W/D ratio, upregulated serum MP-IgM and CRP levels and BALF protein, and enhanced IL-6 and TNF-α levels, which were reversed by BIA or azithromycin treatment, suggesting that BIA attenuated pulmonary inflammatory response in MPP mice. The lung tissue of MPP mice showed upregulated NLRP3, cleaved Caspase-1,Caspase-1, GSDMD-N and GSDMD levels and raised IL-1β and IL-18 levels, and changes were annulled by BIA or azithromycin treatment, suggesting that BIA inhibited the NLRP3/Caspase-1 pathway activation. NLRP3/Caspase-1 pathway activation partially abrogated the alleviative effect of BIA on the pulmonary inflammatory response of MPP mice.

Conclusion: BIA mitigates inflammatory response and lung injury in MPP mice by inhibiting NLRP3/Caspase-1 pathway activation.