International immunopharmacology最新文献

Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and the anti-inflammatory properties of some carbon dots, we developed Radix Isatidis derived carbon dots (RI-CDs) via a hydrothermal method. The RI-CDs can cross the blood-brain barrier (BBB) and were thus evaluated for AD therapy. In vitro, RI-CDs scavenged ROS, inhibited Aβ₄₂ aggregation, protected SH-SY5Y cells, and regulated inflammatory factors. In AD mice, the Morris water maze test and nesting experiment demonstrated that RI-CDs improved the learning and memory ability of mice and improved their nesting ability. Importantly, RI-CDs reduced ROS/Aβ₄₂ in the hippocampus of AD mice, downregulated NLRP3 pathway-related cellular inflammatory factors, and upregulated the expression of BDNF/SYN/PSD95, thereby restoring damaged neurons. These findings demonstrate the compelling neuroprotective efficacy of RI-CDs, highlighting their potential as a promising therapeutic agent for AD.

Neonatal hypoxic-ischemic encephalopathy (HIE) disrupts the blood-brain barrier (BBB) and destroys nascent vessels, thereby amplifying parenchymal loss and chronic neurological disability. Restoring a competent cerebrovasculature is therefore a critical therapeutic goal. Insulin-like growth factor-1 (IGF-1) is already recognized as a neurotrophic factor whose circulating levels correlate with HIE severity and long-term outcome, yet its capacity to drive vascular repair after the insult remains incompletely defined. This study investigated the role of exogenous IGF-1 in BBB repair in neonatal mouse post HI. Our results showed that IGF-1 receptor (IGF-1R) existed on the surface of endothelial cells, which was further upregulated in response to HI challenge. Administration of exogenous IGF-1 apparently attenuated BBB disruption concomitant with a marked enhancement of angiogenesis within the injured cerebral parenchyma. On the contrary, inhibition of the IGF-1R abrogated IGF-1-mediated proangiogenic effects. More importantly, activation of the IGF-1/IGF-1R axis promotes revascularization dependent on upregulation of AKT/eNOS signaling. All together, these findings indicate that IGF-1/IGF-1R axis may represent a potential therapeutic target for blood-brain barrier repair in neonatal HI injury.

Background and aims: Hepatocellular carcinoma (HCC) exhibits limited therapeutic efficacy in current treatment strategies due to high recurrence rates and late-stage diagnosis. This study focuses on the tumor-specific antigen Melanoma-associated antigen A3 (MAGE-A3) to develop a human leukocyte antigen A2-restricted T-cell receptor-engineered T-cell (TCR-T) therapy, systematically evaluating its anti-HCC efficacy and underlying mechanisms.

Methods: MAGE-A3-specific TCR-T cells were engineered by introducing MAGE-A3-specific TCR genes into autologous T cells. Antigen expression and HLA-restricted T-cell recognition were validated, and antigen-specific cytotoxicity against HCC cell lines was assessed in vitro. Antitumor efficacy and safety were evaluated in subcutaneous xenograft models.

Results: Through The Cancer Genome Atlas (TCGA) data analysis and clinical specimen validation, we identified specific MAGE-A3 overexpression in HCC tissues, showing significant correlations with reduced overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) in patients (P < 0.05). Engineered MAGE-A3 antigen-specific TCR-T cells demonstrated significant cytotoxicity and induced target cell apoptosis in in vitro co-culture models. Mechanistic investigations revealed that TCR-T cells regulated apoptotic pathways through dual mechanisms: downregulation of p-AKT phosphorylation levels and activation of cleaved Caspase-3. In subcutaneous xenograft models, TCR-T therapy effectively suppressed tumor progression without observed organ toxicity.

Conclusion: This study provides the first evidence supporting MAGE-A3 as a viable target for TCR-T therapy in HCC, proposing a novel immunotherapeutic strategy for solid tumors.

Background: Among the adverse effects of immunotherapy in cancer patients, immune checkpoint inhibitors (ICIs)-induced myocarditis is the most severe. Pyroptosis is involved in the pathogenesis of various cardiovascular diseases; however, its relationship with ICIs-related myocarditis remains unclear.

Objective: The purpose of this research is to characterize the critical genes mediating pyroptosis in myocarditis related to ICIs, with the goal of informing clinical practice.

Materials and methods: Based on single-cell RNA sequencing and bulk RNA sequencing, this study identified pyroptosis key genes in ICIs-related myocarditis and validated their expression levels and diagnostic value. Single-cell level validation of key genes, trajectory analysis and cellular interactions were also performed. Finally, ICIs-related myocarditis mouse model was established to verify the expression levels of key genes and pyroptosis-related markers.

Results: Integration of multiple bioinformatic analyses identified two pyroptosis key genes in ICIs-related myocarditis: Myd88 and Sqstm1. The expression levels of pyroptosis key genes were significantly higher in the ICIs-related myocarditis group compared to the normal group (P < 0.05 or P < 0.01), and both demonstrated high diagnostic value. Trajectory analysis and cell interaction analysis revealed the interaction strength and relative expression patterns between these two pyroptosis key genes. In the ICIs-related myocarditis mouse model, cardiac injury markers were significantly elevated (P < 0.001 or P < 0.0001), while cardiac function indices were significantly decreased (P < 0.01) compared to the normal group. Quantitative real time polymerase chain reaction and western blot analyses revealed that the expression levels of Myd88 and Sqstm1 were significantly upregulated in the myocarditis group compared to the normal group, at both the mRNA and protein expression levels (P < 0.05 or P < 0.01 or P < 0.0001). Compared with the normal group, the expression levels of pyroptosis-related markers Caspase-1, IL-1β, and GSDMD-N were significantly elevated in the myocarditis group (P < 0.05 or P < 0.01).

Conclusion: Pyroptosis is involved in the pathogenesis of ICIs-related myocarditis, and Myd88 and Sqstm1 may serve as potential biomarkers for future clinical application.

Tumor-associated macrophages (TAMs), highly heterogeneous cells within the tumor microenvironment, can be broadly classified into anti-tumor M1 and pro-tumor M2 phenotypes. Myeloid differentiation protein 2 (MD2), a key immune regulator, has been demonstrated to modulate macrophage inflammatory responses. However, its involvement in TAM reprogramming and the subsequent impact on anaplastic thyroid cancer (ATC) progression remains unclear. In this study, we observed that ATC cells promote macrophage polarization toward the M2 phenotype, accompanied by reduced MD2 expression. Notably, MD2 upregulated the expression of USP15, which was subsequently proved to interact with four and a half LIM domains protein 1 (FHL1) and mediated its deubiquitination, leading to STAT3 inactivation and promoting macrophage polarization toward the M1 phenotype. Furthermore, overexpression of MD2 in macrophages significantly suppressed tumor growth and metastasis through TAM reprogramming. Collectively, these findings highlight a critical role of MD2 in regulating TAM polarization and suggest macrophage-targeted modulation of MD2 as a potential therapeutic strategy for ATC.

Thyroid carcinoma (TC), the most prevalent endocrine malignancy, accounts for 3-4% of global cancer cases and continues to increase in incidence worldwide. Despite advances in diagnosis and treatment, a subset of thyroid cancers remains clinically incurable, underscoring the urgent need to elucidate molecular pathogenesis and identify novel therapeutic targets. Here, we identify complement factor I (CFI) as a key downstream effector of Retinoic acid receptor gamma (RARγ). Mechanistically, RARγ transcriptionally upregulates CFI expression, and analyses of clinical TC specimens demonstrated a strong correlation between RARγ and CFI expression. Conditioned media from RARγ-overexpressing TC cells induced M2-like polarisation of THP-1-derived macrophage-like cells, as evidenced by increased CD206 expression and elevated IL-10 levels-effects that were abolished by CFI neutralisation. In xenograft models, RARγ/CFI-mediated TAM reprogramming drove tumour progression, with RARγ-knockdown tumours exhibiting reduced volumes via macrophage-dependent mechanisms. Importantly, CFI did not affect TC cell-autonomous proliferation, suggesting that its pro-tumoural effects are mediated by the TME rather than directly on tumour cells. Collectively, Our findings establish RARγ/CFI signalling as a microenvironmental rheostat controlling TAM polarisation and provide new insights into the immunobiology of thyroid cancers.

Purpose: Despite significant advances in immunotherapy, lung adenocarcinoma (LUAD) remains challenging to treat due to its low immunogenicity. Platinum-based chemotherapy is a well-established DNA-damaging agent. PARP inhibitor is effective for tumors with DNA repair defects while showing limited efficacy in BRCA-proficient non-small cell lung cancer (NSCLC). This study investigated whether combining a PARP inhibitor with platinum chemotherapy enhances the response to PD-L1 blockade in LUAD and elucidated the underlying mechanism.

Method: Immunoblotting, colony formation assays, real-time PCR, immunofluorescence, flow cytometry, and immunohistochemistry were employed to investigate the underlying mechanisms in cell lines and the tumor microenvironment. The LLC tumor model was used to assess the efficacy of the combination of PARP inhibitors, platinum, and PD-L1 blockade. Clinical relevance was explored using public databases.

Results: PARP inhibitor synergized with platinum to activate the cGAS-STING pathway, leading to an upregulation of PD-L1 expression and stimulation of type I interferon responses in LUAD cells. In LLC mouse models, the triple combination most effectively suppressed tumors, increased dendritic cell and CD8⁺ T-cell infiltration, thereby augmenting anti-tumor immunity. Clinical data linked high PARP1 expression to MDSC infiltration and poor prognosis, and emerging trial evidence supports this combinatorial strategy.

Conclusion: The combination of PARP inhibitors and platinum activates the cGAS-STING pathway, leading to increased infiltration of mature DCs and CD8⁺ T cells, thereby sensitizing NSCLC to anti-PD-L1 therapy. This study presents a promising strategy for treating patients with LUAD with low immunogenicity and poor prognosis.

Background: Neuroinflammation and programmed cell death are two key pathogenic processes that contribute to poor patient outcomes in early brain injury (EBI) following subarachnoid hemorrhage (SAH). Neuronal pyroptosis in SAH has been explored in connection to berberine (BBR), a naturally occurring isoquinoline alkaloid having neuroprotective properties. However, its precise role and molecular mechanisms in this case remain unknown.

Objective: To investigate the protective effects of BBR on EBI following SAH and elucidate its potential molecular mechanisms.

Methods: Network pharmacology and molecular docking techniques were employed to identify core targets and pathways of BBR. In vivo experiments: A mouse SAH model was established via intravascular puncture. Groups included sham surgery, SAH model, BBR treatment, and BBR combined with GSK3β overexpression. Neurological function, cerebral edema, blood-brain barrier permeability, and key molecules in the pyroptosis pathway were assessed using neurological function scoring, brain water content measurement, immunofluorescence, and Western Blot techniques. In vitro experiments simulated SAH injury by exposing HT22 hippocampal neurons to oxygenated hemoglobin (OxyHb). BBR's effects were validated using CCK-8 assays, fluorescence analysis, qPCR, and Western Blot. Mechanistic rescue experiments employed GSK3β agonists.

Results: Network pharmacology predicted GSK3β as a key target of BBR, enriched in the pyroptosis pathway. In vivo experiments demonstrated that BBR significantly improved neurological deficits in SAH mice and reduced cerebral edema and blood-brain barrier disruption while simultaneously inhibiting GSK3β activation in cortical neurons and downstream Caspase-1 cleavage, GSDMD-N fragment generation, and IL-1β maturation. However, intracerebroventricular overexpression of GSK3β reversed these protective effects of BBR. In vitro experiments further confirmed that BBR concentration-dependently inhibits OxyHb-induced pyroptosis and inflammatory responses in HT22 neurons, while GSK3β overexpression significantly antagonizes its protective effects.

Conclusion: BBR alleviates EBI following SAH by targeting GSK3β inhibition, thereby blocking the caspase-1/GSDMD-dependent neuronal pyroptosis pathway.

Kidney tubular cell death caused by elevated blood sugar levels plays a significant role in the progression of diabetic nephropathy (DN). Recent studies have highlighted ferroptosis, a form of regulated cell death, as a critical mechanism underlying tubular cell death in DN. Ubiquitin-specific protease 38 (USP38) has been identified as a key modulator of the ferroptosis process; however, its role in renal tubular cell ferroptosis and DN progression remains unexplored. This study aimed to investigate whether USP38 adjusts ferroptosis in renal tubular cells and its impact on DN progression, elucidating the underlying mechanisms involved. USP38 levels were markedly increased in HK-2 cells stimulated with high glucose (HG) and in the kidneys of diabetic mice. Knockdown of USP38 mitigated HG-induced damage and fibrosis while inhibiting ferroptosis in HK-2 cells; conversely, overexpression of USP38 exacerbated these effects. Further investigations revealed that USP38 modulated the expression of iron metabolism-related proteins, including responsive element binding protein 2 (IREB2), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), and transferrin receptor protein 1 (TfR1). Mechanistically, USP38 was found to directly interact with IREB2 and regulate both its ubiquitination and stability. Moreover, overexpression of IREB2 significantly reversed the inhibitory effect of USP38 silencing on ferroptosis. In vivo experiments demonstrated that USP38 knockdown alleviated renal damage, fibrosis, and inflammation while suppressing iron overload and ferroptosis in DN mice. In conclusion, USP38 mediates renal tubular cell ferroptosis under HG conditions through IREB2-mediated iron overload. Targeting USP38 to prevent tubular epithelial cell ferroptosis may effectively mitigate DN progression, providing a novel regulatory mechanism and potential therapeutic target for this disease.