Frontiers in Immunology最新文献

Background: Chitinase 3-like 1 (CHI3L1) is a prognostic biomarker in multiple sclerosis (MS). However, its clinical application is limited by a lack of standardized detection methods and concerns about preanalytical variability.

Objectives: This study aims to evaluate the impact of preanalytical factors (delayed processing of blood and repeated thawing/freezing) on serum CHI3L1 levels. Additionally, we sought to correlate CHI3L1 blood and cerebrospinal fluid (CSF) levels and identified its cellular source in peripheral blood mononuclear cells (PBMCs) from MS patients.

Methods: We used an in-house Single Molecule Array (Simoa) assay to measure CHI3L1 levels in serum, plasma, and CSF from MS patients and controls. The source of CHI3L1 production in PBMCs was determined by flow cytometry.

Results: A strong correlation was found between serum, plasma, and CSF CHI3L1 levels. Serum CHI3L1 levels remained stable with delayed processing up to 6 hours and for up to three freeze-thaw cycles. Monocytes, particularly classical monocytes (CD14⁺⁺CD16^- cells), were identified as the main producers of CHI3L1 in PBMCs.

Conclusions: The study establishes preanalytical guidelines for sCHI3L1 assessment and confirms that blood levels can be as informative as CSF levels. This provides groundwork for the standardized use of CHI3L1 as a biomarker in managing MS patients.

With advances in microbial sequencing technology, the role of microorganisms in cancer development and treatment has been increasingly explored. The gut microbiota, as a key shaper of both innate and adaptive immunity, is believed to migrate from the gut and colonize the pancreas, thereby influencing the tumor microenvironment(TME) of pancreatic cancer. Pancreatic cancer exhibits treatment resistance due to its immunosuppressive TME and high interstitial density. Multiple sequencing analyses of pancreatic tumor tissues have revealed that alterations in the tumor-associated microbiota are associated with prognosis and treatment response, suggesting that the microbiota may serve as a complementary modality in immunotherapy. This paper describes potential pathways by which the gut microbiota can migrate to the pancreas and analyzes changes in tumor microbiota composition. It also identifies microbiota types associated with prognosis, and summarizes treatment strategies leveraging the gut-pancreas axis to enhance the personalization and precision of care. It critically examines the limitations of existing research, and aims to leverage microbiome ecology to overcome the immune -suppressive barrier in pancreatic cancer and improve patient outcomes.

Optic nerve injury, encompassing conditions such as glaucoma, optic neuritis, and traumatic optic neuropathy, is a major cause of irreversible vision loss. Traditional broad-spectrum anti-inflammatory treatments have shown limited efficacy, highlighting the need for precision-based therapeutic approaches grounded in the underlying pathological mechanisms. As the primary immune cells of the central nervous system (CNS), microglia play a crucial role in regulating neuroinflammation following optic nerve injury. This review provides a comprehensive overview of the mechanisms governing microglial neuroinflammatory regulation, including early inflammatory signal recognition mediated by damage-associated molecular patterns (DAMPs), dynamic transcriptional networks regulating polarization between pro-inflammatory and pro-repair phenotypes, bidirectional modulation of phagocytic clearance by the complement system, and the complex multicellular interactions among microglia, astrocytes, and Müller cells. The concept of conditioning injury conditioning injury (intraocular inflammatory stimulation) has revealed the dual nature of neuroinflammatory responses: through temporal polarization shifts, microglia can both release neurotoxic mediators that worsen injury and secrete neurotrophic factors that promote axonal regeneration and myelin repair. This shift from traditional broad-spectrum anti-inflammatory strategies to precision functional modulation forms the basis for emerging therapeutic approaches, including PPARγ pathway activation, selective complement system targeting, and time-dependent modulation. We also assess the potential of advanced technologies, such as nanodelivery systems, single-cell analysis, and molecular imaging, in precision diagnosis and treatment. Finally, we critically examine the limitations of current research, including interspecies variability, model constraints, and clinical translation barriers, and discuss the translational potential of microglia-targeted therapies in protecting and restoring clinically meaningful visual function.

Introduction: SLE is a chronic autoimmune disease characterized by immune system dysregulation, including aberrant activation of B and T lymphocytes and overproduction of proinflammatory cytokines such as IL-21. Through the STAT3 signaling pathway, this cytokine plays a key role in SLE-promoting autoantibody production and immune imbalance. It has been reported that miRNAs, such as miR-155 and miR-21, could be overexpressed in SLE and contribute to the STAT3 pathway dysregulation. We aimed to analyze the association between miR-155 and miR-21 and the expression of SOCS1, PTEN, PIAS3, and IL21 in PBMC from SLE patients.

Materials and methods: PBMC isolation was performed by density gradient centrifugation using Histopaque-1077, culture overnight, and seeded at a concentration of 1x10⁶ cells/mL in 24-well flat-bottom cell culture plates for subsequent stimulation with 0.5 μg/mL ionomycin and 2.5 μg/mL PMA. The expression levels of miR-155, miR-21, SOCS1, PTEN, PIAS3, and IL21 were measured using the RT-qPCR technique. Western blotting determined the expression of SOCS1, PTEN, PIAS3, IL-21, and p-STAT3 proteins. IL-17A levels in cell culture supernatant were determined using ELISA to assess cell stimulation.

Results: Our results showed an increased expression of miR-155 and miR-21 in SLE patients compared to HC in both, stimulated and non-stimulated PBMC. The increased miR-155 and miR-21 expression were associated with a decreased gene expression of SOCS1 and PTEN. The IL21 expression was observed in stimulated PBMC with higher levels in SLE patients. These also showed lower expression of SOCS1, PTEN, and PIAS3, while levels of IL-21 were increased in total protein from PBMC, culture cell supernatants and plasma levels. Overall, p-STAT3 was increased in the PBMC of SLE patients. Finally, miR-21 inversely correlated with PIAS3 and PTEN and miR-155 with SOCS1.

Discussion: These findings highlight the association between miR-155 and miR-21 with target genes SOCS1, PTEN, and PIAS3, that may contribute to the aberrant activation of the STAT3 pathway and the overproduction of IL-21 in SLE patients.

Introduction: Systemic sclerosis (Scleroderma; SSc) is associated with high morbidity and mortality, particularly in patients with pulmonary arterial hypertension (SSc-PAH) and pulmonary fibrosis (SSc-PF). Effective risk stratification and treatment of SSc remains a significant challenge. This proof-of-concept study aimed to identify potential biomarkers capable of distinguishing between three SSc patient groups, defined by no pulmonary involvement (SSc-NLD; n=30), SSc-PAH (n=30), SSc-PF (n=30) compared to healthy controls (HC; n=30).

Methods: The study employed Olink-based proteomics using the Cardiovascular II and Immuno-oncology panels, and untargeted metabolomic profiling using Ultra-high Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS), to discover distinct molecular signatures.

Results: Proteomics analysis revealed significantly elevated levels of MCP-1, MCP-3, and MCP-4 in SSc-PF compared to all other groups. However, no robust discriminatory cytokines were identified for SSc-PAH or SSc-NLD. Validation of systemic MCP-1 and IL-6 by ELISA supported the proteomics findings. IL-33 levels were found to be reduced in the SSc-PAH group. Increased levels of pro-inflammatory sIL-6R were also identified in SSc-PAH and SSc-PF, indicating shared inflammatory pathways. Protein-protein interaction analyses demonstrated greater network complexity in SSc-PF, with pathway analysis suggesting overlapping biological mechanisms across pulmonary groups. Metabolomics analysis uncovered a unique panel of metabolites altered exclusively in SSc-PAH, including quinolinate, dimethylarginines, hydroxyasparagine and orotidine. In contrast, no metabolites were uniquely discriminatory for SSc-PF or SSc-NLD. Metabolite-metabolite interaction networks revealed nicotinate and nicotinamide metabolism as the more significantly enriched metabolic pathways in SSc-PAH. Correlation analyses identified distinct protein-metabolite profiles across groups. Of note is the loss of IL-33-related metabolic associations specific to SSc-PAH.

Discussion: This study identified a candidate biomarker panel comprising three cytokines and ten metabolites capable of differentiating between SSc-PAH, SSc-PF, SSc-NLD, and HC. Biomarkers of SSc-PAH were linked to nicotinate and nicotinamide, as well as tryptophan metabolism, whereas those of SSc-PF reflected immune cell infiltration and fibrosis. These findings highlight the potential biomarker panels for diagnosis and targeted therapeutic development.

Purpose: Abscopal effects (AbE) during combined radiotherapy (RT) and immune checkpoint inhibition (ICI) represent a potential mechanism for systemic tumor control, yet sex-specific differences in these responses remain largely unexplored. We investigated sex-associated signals in outcomes of combined RT-ICI in a multicenter cohort. We analyzed the incidence of AbE and survival outcomes with respect to clinical and biomedical markers.

Methods: In this observational multicenter study, patients with metastatic solid tumors receiving RT-ICI and showing at least one non-irradiated lesion (NIL), assessed using iRECIST criteria, were analyzed. Abscopal response (AR) was defined as ≥30% reduction in NIL size, abscopal progression (AP) as ≥20% increase, and abscopal control (AC) as changes within this range.

Results: Among 3,773 screened patients, 142 met the inclusion criteria (62% male, median age 62 years; 38% female, median age 58 years). AR and AC occurred more frequently in females (24% vs. 14%, 35% vs. 31%). While OS showed no significant difference (p=0.81), Cox regression analyses revealed significant associations of a longer ICI-to-RT-interval (males: HR = 0.903 [0.833-0.978], p=0.012; females: HR = 0.748 [0.621-0.900], p=0.002) and a BMI ≥25 kg/m² with survival in both sexes (males: HR = 4.282 [1.473-12.446], p=0.008; females: HR = 4.801 [1.182-19.502], p=0.028 with survival in both sexes). Elevated C-reactive protein (CRP) (≥5 mg/L) showed prognostic significance only in males (HR = 4.764 [1.184-19.170], p=0.028).

Conclusion: Our findings suggest the possibility of sex-specific patterns in AbE occurrence. Additionally, our analyses identified sex-associated prognostic factors, including the importance of ICI-to-RT interval and BMI in both sexes and the male-specific prognostic value of CRP. These observations warrant further research and consideration in designing personalized RT-ICI combination strategies.

[This corrects the article DOI: 10.3389/fimmu.2025.1723346.].

Background: Abdominal aortic aneurysm (AAA) is a severe vascular disease that can lead to rupture and life-threatening hemorrhage. The role of ferroptosis in AAA pathogenesis remains insufficiently understood. This study aims to investigate the role of ferroptosis in AAA by identifying ferroptosis-associated molecular subtypes and examining their relationship with immunological characteristics using an artificial neural network (ANN) model.

Methods: We analyzed three publicly available datasets (GSE7084, GSE47472, and GSE57691) to identify differentially expressed ferroptosis-related genes (FRGs) and employed consensus clustering to classify AAA samples into two subtypes. Immune infiltration was assessed with the CIBERSORT algorithm, and a diagnostic artificial neural network (ANN) model based on subtype-specific genes was developed to discriminate ferroptosis-associated molecular subtypes and derive the NeuraAAA score.

Results: Nine differentially expressed FRGs were identified, and the model incorporated three key genes (oncostatin M, heme oxygenase-1, and interleukin-6), achieving high diagnostic accuracy (AUC = 0.988). Consensus clustering stratified AAA samples into two ferroptosis-associated subtypes with distinct immune profiles, with the C1 subtype showing higher immune infiltration and immune scores than C2. The derived NeuraAAA score was elevated in the immune-enriched subtype and correlated with immune-cell infiltration, and a nomogram integrating NeuraAAA and immune score showed good calibration. Immunofluorescence confirmed increased expression of all three genes in AAA specimens.

Conclusion: Our study reveals the heterogeneous role of ferroptosis in AAA pathogenesis, demonstrating that ferroptosis-associated subtypes are linked to variations in the immune microenvironment. These findings provide new insights into AAA pathophysiology and suggest potential targets for subtype-specific therapeutic strategies, contributing to advances in precision medicine for AAA treatment.

Renal cell carcinoma (RCC) is an immunogenic tumor in which tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) represent a functionally important component of the tumor microenvironment. Recent studies have revealed pronounced phenotypic heterogeneity of RCC-infiltrating neutrophils, including interferon-responsive, immunosuppressive PMN-MDSC-like, pro-angiogenic, and NET-forming subsets that cannot be adequately described by the classical N1/N2 model. Their polarization is shaped by ELR⁺ CXC chemokines (CXCL1, CXCL8), cytokine signals, systemic inflammation, hypoxia driven by VHL/HIF pathways, and tumor-intrinsic oncogenic alterations such as PTEN loss, ERβ- and c-Myc-dependent programs, as well as epigenetic remodeling. TANs exert predominantly pro-tumor functions in RCC, promoting T-cell exclusion and exhaustion, supporting angiogenesis and stromal remodeling, and facilitating epithelial-mesenchymal transition, venous invasion and metastasis. NETs, enriched in hypoxic and necrotic tumor regions and in venous tumor thrombi, further contribute to vascular occlusion, metastatic dissemination and local immune dysfunction, and are reflected by distinct transcriptional signatures. Clinically, high TAN density, activation markers and neutrophil/NET-associated gene signatures are consistently associated with aggressive tumor behavior, early recurrence, poor survival and resistance to VEGF-TKIs and immune checkpoint inhibitors. Emerging data also link neutrophil-rich stromal inflammation with the tumor resident microbiome, suggesting composite TAN-microbiome biomarkers for refined risk stratification. In this review, we summarize current knowledge on phenotypic diversity, regulatory circuits and functional programs of TANs and NETs in RCC, and discuss their prognostic and predictive significance, as well as therapeutic strategies aimed at chemokine blockade, complement modulation, NET inhibition and neutrophil re-education.

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by chronic neuroinflammation and loss of dopaminergic neurons. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) selectively targets dopaminergic neurons, effectively replicating the pathological features of PD. Lupeol, a natural pentacyclic triterpenoid, has been shown to exhibit neuroprotective properties in various models by reducing oxidative stress, inflammation, and apoptosis. This study aimed to investigate the neuroprotective effects of lupeol in an MPTP-induced mouse model of PD.

Methods: Male mice were administered MPTP (30 mg/kg, i.p.) for seven days to induce PD-like pathology. Lupeol (50 mg/kg) was administered as a potential therapeutic intervention. Behavioral assessments were conducted to evaluate motor function. Biochemical analyses were performed to measure dopamine and tyrosine hydroxylase (TH) levels. Immunohistochemical and molecular approaches were used to assess glial activation, oxidative stress, and apoptotic signaling pathways in the substantia nigra pars compacta (SNpc) and striatum.

Results: Lupeol treatment significantly improved MPTP-induced motor impairments and restored dopamine and TH levels. Additionally, lupeol reduced neuroinflammation, by decreasing microglial activation, astrocyte reactivity, and lower levels of inflammatory mediators. Oxidative stress markers, including reactive oxygen species (ROS) and lipid peroxidation (LPO), were diminished in SNpc and striatum following lupeol treatment. Furthermore, lupeol upregulated antioxidant defense mechanisms by increasing the expression of Nrf-2 and HO-1. Apoptotic markers, such as Cytochrome C, Bax, and Caspase-3, were downregulated, indicating reduced neuronal apoptosis.

Conclusion: The current study suggests that lupeol exerts neuroprotective effects by inhibiting glial cell activation, thereby reducing neuroinflammation, oxidative stress, and apoptosis in an MPTP-induced PD mouse model.