International immunopharmacology最新文献

Background

Triple-negative breast cancer (TNBC) is prone to relapse due to the lack of effective therapeutic targets. Macrophages are the most abundant immune cells in the tumor microenvironment (TME) of breast cancer. Targeting the cross-talk between macrophages and cancer cells provides a more efficient strategy for anti-tumor therapy. Toll-like receptors (TLRs) are important players involved in macrophage activation, and TLR agonists are known to play roles in cancer therapy. However, the combination strategy of TLR agonists with chemotherapy drugs is still not well characterized.

Methods

RT-PCR and Western blot were used to detect the expression of TLRs. The communication between breast cancer cells and macrophages were determined by co-culture in vitro. Tumor cells proliferation and migration were investigated by MTT assay and scratch wound assay. The effects of drug combinations and toxic side effects were assessed by immunohistochemistry and Hematoxylin & Eosin staining.

Results

Expression of TLR3 and TLR4 were lower in breast tumor tissues compared with adjacent normal tissues. Patients with higher TLR3 or TLR4 expression levels had a better prognosis than those with lower expression levels. TLR3/4 expression was significantly inhibited when breast cancer cells MDA-MB-231 and E0771 were conditioned-cultured with macrophages in vitro and was also inhibited by pirarubicin (THP). However, the combination of TLR agonists and THP could reverse this response and inhibit the proliferation and migration of breast cancer cells. Additionally, this combination significantly reduced the tumor volume and weight in the murine model, increased the expression of TLR3/4 in mouse breast tumors.

Conclusions

Our results provide new ideas for the combination strategy of THP with TLR agonists which improves prognosis of breast cancer.

Multiple sclerosis (MS) is a neurodegenerating autoimmune disease with no clinical cure currently. The calcium-binding protein S100A4 has been demonstrated to exert regulatory roles in inflammatory disorders including MS. However, the precise mechanisms by which S100A4 regulates neuroinflammation in MS remains unknown. To investigate the regulatory effect of S100A4 on microglial inflammation and its impact on neuroinflammation, the mouse-derived microglia cell line BV2 cells were infected with lentivirus to knockout S100A4 for in vitro studies. Wild-type (WT) and S100A4^-/- mice were induced to develop experimental autoimmune encephalomyelitis (EAE), an animal model of MS, for in vivo investigation. Results indicated that the frequencies of microglia in the spinal cord and brain and the expression of S100A4 in these tissues varied kinetically along with the progression of the disease in mice with EAE. S100A4^-/- mice presented ameliorated clinical scores of EAE and exhibited less severe EAE signs, including inflammatory cell infiltration in the spinal cord and brain and demyelination of the spinal cord. Moreover, these mice demonstrated overall reduced levels of inflammatory cytokines in the spinal cord and brain. Compromised systematic inflammatory responses including circulating cytokines and frequencies of immune cells in the spleen were also observed in these mice. In addition, both exogenous and endogenous S100A4 could promote the microglial inflammation, affect the polarization of microglia and enhance inflamed microglia-mediated apoptosis of neuronal cells through TLR4/NF-κB signaling pathway. Thus, S100A4 may participate in the regulation of neuroinflammation at least partly through regulating the inflammation of microglia.

Background

Immunoglobulin A vasculitis (IgAV) is a kind of systemic vasculitis mediated by IgA immune complexes (IgA-ICs). Soluble CD89-IgA complex (sCD89-IgA) as a type of IgA-IC associated with renal involvement in IgAV, the ability of blood sCD89-IgA as a biomarker to predict renal or multi-organ involvement in children with IgAV is not evident, and this study mainly focused on this.

Methods

The clinical characteristics and blood samples of 57 pediatric patients with IgAV were collected. ELISA was used to detect plasma IgA-ICs and sCD89-IgA levels. Serum IgA levels were detected by Nephelometry method. Statistical analysis was conducted to analyze the relationship between sex, age, serum IgA levels, plasma IgA-ICs levels, plasma sCD89-IgA levels and the involvement of multiple organs (except skin) including kidneys in these patients.

Results

Compared to patients with simple skin involvement, patients with multi-organ involvement, especially kidneys, had higher levels of plasma IgA-ICs and sCD89-IgA, and the statistical difference was significant. In addition, a high level of plasma sCD89-IgA was a high-risk factor for patients to develop multi-organ or renal involvement in addition to the skin. ROC curve analysis showed that the AUC was 0.861 (Sensitivity: 83 %, Specificity: 88 %, p < 0.0001) when plasma sCD89-IgA predicted multi-organ involvement, and AUC 0.926 (Sensitivity: 94 %, Specificity: 88 %, p < 0.0001) for predicting renal involvement.

Conclusions

The results suggested that plasma sCD89-IgA may be a potential biomarker for predicting multi-organ involvement (in addition to skin), especially renal involvement in IgAV pediatric patients.

Schisandra chinensis, a traditional Chinese medicine, has been widely applied in China to treat diabetes and its complications. The aim of this study was to discover the active compounds and explain related molecular mechanism contributing to the anti-diabetic effect of Schisandra chinensis. Herein, the therapeutic effects of Schisandra chinensis extracts on type 2 diabetes mellitus (T2DM) were firstly confirmed in vivo. Subsequently, various lignans were isolated from Schisandra chinensis and tested for hypoglycemic activity in palmitic acid-induced insulin-resistant HepG2 (IR-HepG2) cells. Among these lignans, R-biar-(7S,8R)-6,7,8,9-tetrahydro-1,2,3,12,13,14-hexamethoxy-7,8-dimethyl-7-dibenzo [a, c] cyclooctenol (compound 2) and Gomisin A (compound 4) were identified significantly increased the glucose consumption in IR-HepG2 cells. Meanwhile, compounds 2 and 4 activated the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) pathway, which regulates glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pase), essential for gluconeogenesis and glucose uptake. These compounds also inhibited the nuclear factor-κB (NF-κB) signaling pathway, reducing interleukin-6 (IL-6) levels. Importantly, the hypoglycemic effects of compounds 2 and 4 were diminished after Toll-like receptor 4 (TLR4) knockdown. Cellular thermal shift assays confirmed increased TLR4 protein stability upon treatment with these compounds, indicating direct binding to TLR4. Furthermore, TLR4 knockdown reversed the effects of compounds 2 and 4 on the NF-κB and IRS-1/PI3K/AKT pathways. Taken together, compounds 2 and 4 alleviate IR by targeting TLR4, thereby modulating the NF-κB and IRS-1/PI3K/AKT pathways. These findings suggest that compounds 2 and 4 could be developed as therapeutic agents for T2DM.

Acinetobacter baumannii, is among the highest priority bacteria according to the WHO categorization which necessitate the exploration of alternative strategies such as vaccination. OmpA, BamA, and Omp34 are assigned as appropriate antigens to serve in vaccine development against this pathogen. Experimentally validated exposed epitopes of OmpA and Omp34 along with selected exposed epitopes predicted by an integrative in silico approach were represented by the barrel domain of BamA as a scaffold. Among the 8 external loops of BamA, 5 loops were replaced with selected loops of OmpA and Omp34. The designed antigen was analyzed regarding the physicochemical properties, antigenicity, epitope retrieval, topology, structure, and safety. BamA is a two-domain OMP with a 16-stranded barrel in which L4, L6, and L7 were the longest loops of BamA in order. The designed antigen consisted of 478 amino acids with antigen probability of 0.7793. The novel antigen was a 16-stranded barrel. No identical 8-meric peptides were found in the human proteome against the designed antigen sequence. The designed construct was safe regarding the allergenicity, toxicity, and human proteome reactivity. The designed antigen could develop higher protection against A. baumannii in comparison to either OmpA, BamA, or Omp34 alone.

MDSCs (myeloid-derived suppressor cells) are crucial for immune system evasion in cancer. They accumulate in peripheral blood and tumor microenvironment, suppressing immune cells like T-cells, natural killer cells and dendritic cells. They promote tumor angiogenesis and metastasis by secreting cytokines and growth factors and contribute to a tumor-promoting environment. The accumulation of MDSCs in cancer patients has been linked to poor prognosis and resistance to various cancer therapies. Targeting MDSCs and their immunosuppressive mechanisms may improve treatment outcomes and enhance immune surveillance by developing drugs that inhibit MDSC function, by preventing their accumulation and by disrupting the tumor-promoting environment. This review presents a detailed overview of the MDSC research in cancer with regulation of their development and function. The relevance of MDSC as a prognostic and predictive biomarker in different types of cancers, along with recent advancements on the therapeutic approaches to target MDSCs are discussed in detail.

Background

Germ cell tumors (GCTs) are a heterogeneous group of cancers associated with a favorable prognosis when treated with platinum-based chemotherapy. However, patients with platinum-refractory GCTs face limited options and poorer outcomes, necessitating innovative treatment approaches. This study aims to evaluate the clinical outcomes and identify prognostic factors associated with immunotherapy-based treatments in this challenging patient population.

Methods

This retrospective analysis included individuals with platinum-refractory GCTs treated with immunotherapy between 2017 and 2023. Clinical outcomes, safety, and biomarkers were analyzed.

Results

The study included 37 male patients with a median age of 26 years (range: 18–65). The overall response rate was 24.32 %, with a median progression-free survival (PFS) and overall survival (OS) of 4.67 months and 22.67 months, respectively. Patients with both serum levels of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) below 100 (AFP & hCG < 100) demonstrated significantly better PFS and OS. Multivariate analysis indicated that lower serum tumor marker levels (AFP & hCG < 100) and treatment initiation at earlier lines were significantly associated with improved PFS. Notably, genomic analysis revealed that one patient with an MDM4 mutation experienced hyperprogression after the initiation of immunotherapy. Immune-related adverse events occurred in two patients: one developed grade 1 hyperthyroidism, and the other experienced grade 2 immune-related pneumonitis.

Conclusions

Immunotherapy offers a promising treatment option for selected patients with platinum-refractory GCTs, demonstrating moderate response rates and potential survival benefits in a real-world scenario. Identifying specific prognostic factors may help tailor treatment strategies and enhance outcomes in this challenging patient cohort.

Background

In sepsis-associated encephalopathy (SAE), the activation of microglial cells and ensuing neuroinflammation are important in the underlying pathological mechanisms. Increasing evidence suggests that the protein Piezo1 functions as a significant regulator of neuroinflammation. However, the influence of Piezo1 on microglial cells in the context of SAE has not yet been determined. This study aims to investigate the role of Piezo1 in microglial cells in the context of SAE.

Methods

By inducing cecal ligation and puncture (CLP), a mouse model of SAE was established, while the control group underwent a sham surgery in which the cecum was exposed without ligation and puncture. Piezo1 knockout mice were employed in this study. Morris water maze tests were conducted between Days 14 and 18 postop to assess both the motor activity and cognitive function. A proteomic analysis was conducted to assess the SAE-related pathways, whereas a Mendelian randomization analysis was conducted to identify the pathways associated with cognitive impairment. Dual-label immunofluorescence and flow cytometry were used to assess the secretion of inflammatory factors, microglial status, and oligodendrocyte development. Electron microscopy was used to evaluate axonal myelination. A western blot analysis was conducted to evaluate the influence of Piezo1 on oligodendrocyte ferroptosis.

Results

The results of the bioinformatics analysis have revealed the significant involvement of CCL25 in the onset and progression of SAE-induced cognitive impairment. SAE leads to cognitive dysfunction by activating the microglial cells. The release of CCL25 by the activated microglia initiates the demyelination of oligodendrocytes in the hippocampus, resulting in ferroptosis and the disruption of hippocampal functional connectivity. Of note, the genetic knockout of the Piezo1 gene mitigates these changes. The treatment with siRNA targeting Piezo1 effectively reduces the secretion of inflammatory mediators CCL25 and IL-18 by inhibiting the p38 pathway, thus preventing the ferroptosis of oligodendrocytes through the modulation of the CCL25/GPR78 axis.

Conclusion

Piezo1 is involved in the activation of microglia and demyelinating oligodendrocytes in the animal models of SAE, resulting in cognitive impairment. Consequently, targeting Piezo1 suppression can be a promising approach for therapeutic interventions aimed at addressing cognitive dysfunction associated with SAE.

Background

Schizophrenia (SCZ) is a heterogeneous psychiatric disorder that is poorly treated by current therapies. Emerging evidence indicates that SCZ is closely correlated with a persistent neuroinflammation. α-linolenic acid (ALA) is highly concentrated in the brain and represents a modulator of the immune system by decreasing the inflammatory response in chronic metabolic diseases. This study was first designed to investigate the potential role of dietary ALA on cognitive function and neuroinflammation in mice with SCZ.

Methods

In vivo, after 2 weeks of modeling, mice were treated with dietary ALA treatment for 6 weeks. In vitro, inflammation model was created using lipopolysaccharide as an inducer in BV2 microglial cells.

Results

Our results demonstrated that ALA alleviated cognitive impairment and enhanced synaptic plasticity in mice with SCZ. Moreover, ALA mitigated systematic and cerebral inflammation through elevating IL-10 and inhibiting IL-1β, IL-6, IL-18 and TNF-α. Furthermore, ALA notably inhibited microglia and pro-inflammatory monocytes, as well as microglial activation and polarization. Mechanistically, ALA up-regulated the expressions of G protein coupled receptor (GPR) 120 and associated β-inhibitor protein 2 (β-arrestin2), accompanied by observable weakened levels of transforming growth factor-β activated kinase 1 (TAK1), NF-κB p65, cysteine proteinase-1 (caspase-1), pro-caspase-1, associated speck-like protein (ASC) and NLRP3. In vitro, ALA directly restrained the inflammation of microglia by decreasing the levels of pro-inflammatory factors and regulating microglial polarization via GPR120-NF‐κB/NLRP3 inflammasome signaling pathway, whereas AH7614 definitely eliminated this anti-inflammatory effect of ALA.

Conclusion

Dietary ALA ameliorates microglia-mediated neuroinflammation by suppressing the NF-κB/NLRP3 pathway via binding GPR120-β-arrestin2.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that affects multiple organs and systems in the human body, often leading to disability. Its pathogenesis is complex, and the long-term use of traditional anti-rheumatic drugs frequently results in severe toxic side effects. Therefore, the search for a safer and more effective antirheumatic drug is extremely important for the treatment of RA. As important immune cells in the body, macrophages are polarized. Under pathological conditions, macrophages undergo proliferation and are recruited to diseased tissues upon stimulation. In the local microenvironment, they polarize into different types of macrophages in response to specific factors and perform unique functions and roles. Previous studies have shown that there is a link between macrophage polarization and RA, indicating that certain active ingredients can ameliorate RA symptoms through macrophage polarization. Notably, Traditional Chinese medicine (TCM) monomer component and compounds demonstrate a particular advantage in this process. Building upon this insight, we reviewed and analyzed recent studies to offer valuable and meaningful insights and directions for the development and application of anti-rheumatic drugs.