Cellular & Molecular Immunology[JOURNAL]
Sun
200 papers
Restoring NR4A3 function in neutrophils alleviates sepsis by limiting NF-κB-dependent NETs formation and organ damage.
Li S, Liu C, Wu C … +1 more , Liu Z
Mol Immunol · 2026 Jan · PMID 41443148 · Publisher ↗
BACKGROUND: Sepsis, a life-threatening condition, involves excessive neutrophil extracellular traps (NETs) contributing to organ damage. The role of orphan nuclear receptor NR4A3 in modulating neutrophil NETosis via NF-κ...
BACKGROUND: Sepsis, a life-threatening condition, involves excessive neutrophil extracellular traps (NETs) contributing to organ damage. The role of orphan nuclear receptor NR4A3 in modulating neutrophil NETosis via NF-κB during sepsis is poorly understood. This study aimed to elucidate NR4A3's function and therapeutic potential. METHODS: Single-cell RNA sequencing analysis was performed using GSE175453 and GSE167363 from GEO database, involving PBMCs from septic patients and controls. In vitro, ATRA-differentiated HL-60 neutrophils with NR4A3 overexpression were LPS-stimulated. In vivo, a cecal ligation and puncture (CLP) sepsis mouse model received AAV-mediated NR4A3 overexpression. Key readouts included NR4A3 expression, NF-κB activation, NETs markers (NE, CitH3, PADI4, MPO-DNA), inflammatory cytokines (TNF-α, IL-1β, IL-6), ROS generation, and intestinal tissue pathology. RESULTS: scRNA-seq analysis revealed significant NR4A3 downregulation in neutrophils from septic patients. In vitro, NR4A3 overexpression in neutrophils significantly attenuated LPS-induced NF-κB (p65) activation, NETs formation, inflammatory cytokine production, and ROS generation. In vivo, AAV-mediated NR4A3 overexpression in CLP-induced septic mice ameliorated intestinal inflammation, suppressed p65 phosphorylation and NETs-related markers in the intestine, and reduced systemic inflammatory cytokine levels. CONCLUSION: Our findings demonstrate that NR4A3 exerts a protective role in sepsis by inhibiting the NF-κB signaling pathway in neutrophils, thereby suppressing excessive NETs formation and the associated inflammatory cascade. Thus, NR4A3 represents a promising therapeutic target for mitigating NET-driven pathology in sepsis.
Indole-3-propionic acid exerts radio-protective effects by modulating Wnt1/STAT3 pathway to alleviate oxidative stress and neuroinflammation in microglia.
Si Y, Zhang B, Wei J … +3 more , Li M, Liu Y, Ma H
Mol Immunol · 2026 Jan · PMID 41435624 · Publisher ↗
Radiation-induced delayed brain injury (RIBI) refers to structural and functional brain alterations that develop several months to years after exposure to ionizing radiation (IR). Microglia activation-mediated neuroinfla...
Radiation-induced delayed brain injury (RIBI) refers to structural and functional brain alterations that develop several months to years after exposure to ionizing radiation (IR). Microglia activation-mediated neuroinflammation, as well as oxidative stress, constitutes a key factor contributing to RIBI. Indole-3-propionic acid (IPA) is an indole metabolite specifically produced by the tryptophan metabolism of gut microbiota. It can cross the blood-brain barrier and modulate the central nervous system (CNS). In order to explore the protective mechanism of IPA on IR-induced cerebral function, we studied the effect of IPA on the activation of BV2 microglia in vitro. The experimental results show that IPA can suppress the oxidative stress and inflammation of microglia, which is represented as upregulating the expression of antioxidant genes (Hmox1, Ho-1, and Nqo1), and reducing the mRNA levels of pro-inflammatory factors (Tnf-α, Il-6, Inos, and Nox2). This protective effect may be related to the inhibition of Wnt1 expression and STAT3 phosphorylation (p-STAT3 Y705; p = 0.0008) in microglia. Additionally, it was found that IPA could alleviate the IR-induced neuroinflammation and synaptic damage of mice, as evidenced by reduced serum TNF-α and IL-6 levels and widened postsynaptic density (PSD) thickness (p = 0.0239). Collectively, this study provides novel insights into the potential application of IPA in the therapeutic intervention of radiation-induced brain injury.
Isoimperatorin inhibits cell proliferation and induces apoptosis via regulating PI3K/AKT pathway in acute lymphoblastic leukemia.
Xiao J, Wang Y
Mol Immunol · 2026 Jan · PMID 41418420 · Publisher ↗
OBJECTIVES: This study aims to explore whether isoimperatorin (ISOIM) regulates the malignant phenotype of T‑cell acute lymphoblastic leukemia (T-ALL) cells through the PI3K/AKT pathway and programmed cell death ligand-1...
OBJECTIVES: This study aims to explore whether isoimperatorin (ISOIM) regulates the malignant phenotype of T‑cell acute lymphoblastic leukemia (T-ALL) cells through the PI3K/AKT pathway and programmed cell death ligand-1 (PD-L1). METHODS: Through in vitro experiments, ISOIM on T-ALL cell proliferation and apoptosis was evaluated using the cell counting kit-8 and EdU assays, flow cytometry, and TUNEL staining. Network pharmacology, molecular docking, and functional enrichment analyses were conducted to analyze the underlying mechanisms of ISOIM. Changes in apoptosis-related proteins, PD-L1 protein, and PI3K/AKT pathway-related proteins were assessed by western blotting. RESULTS: ISOIM inhibited T-ALL cell proliferation, promoted apoptosis, decreased Bcl-2 levels, and increased C-caspase-3 and Bax levels. KEGG and GO enrichment analyses indicated that the overlapping targets between ISOIM and ALL were related to the PD-1 checkpoint and PI3K/AKT pathway. Molecular docking analysis showed good binding between ISOIM and PIK3CA (also known as PI3K). ISOIM reduced PD-L1, p-PI3K, p-AKT, and p-mTOR levels. Moreover, the PI3K/AKT pathway activator 740 Y-P reversed the inhibitory effect of ISOIM on PD-L1 expression and the malignant behavior of T-ALL cells. CONCLUSIONS: ISOIM inhibited the malignant behavior of T-ALL cells and reduced PD-L1 levels by suppressing the PI3K/AKT pathway. This study provides a theoretical basis for developing novel treatment strategies for ALL.
The genetic characteristics of Pahepcidin1 and Pahepcidin2 in silver pomfret (Pampus argenteus) and their antibacterial functions in innate immunity.
Fang Q, Wang R, Liu X … +5 more , Wang Y, Xie Q, Guo C, Yuan M, Wang X
Mol Immunol · 2026 Jan · PMID 41418418 · Publisher ↗
Hepcidins are a class of cysteine-rich antimicrobial peptides that exert significant impacts in response to a variety of pathogens. In this study, two hepcidins were identified from silver pomfret (Pampus argenteus), nam...
Hepcidins are a class of cysteine-rich antimicrobial peptides that exert significant impacts in response to a variety of pathogens. In this study, two hepcidins were identified from silver pomfret (Pampus argenteus), namely Pahepcidin1 and Pahepcidin2. Our findings revealed that Pahepcidin1 consists of a 267 open reading frame (ORF) encoding 91 amino acids, while Pahepcidin2 consists of 246 bp ORF encoding 81 amino acids. Sequence comparison between Pahepcidins and other homologous genes demonstrated the presence of eight conserved cysteines in the C-terminus region of Pahepcidin1 and six cysteine residues in the C-terminus region of Pahepcidin2. Phylogenetic analysis indicated that both Pahepcidin1 and Pahepcidin2 clustered with other fish homologues, respectively. The results of tissue-specific expression analysis showed that Pahepcidins exhibited the highest expression level in the liver; moreover, the expression level of Pahepcidin1 in silver pomfret liver cells (PaL cells) was also significantly increased after stimulation with lipopolysaccharide (LPS), polyinosinic-polycytidylic acid (poly I:C), and Staphylococcus aureus (S. aureus). Meanwhile, this study verified the antibacterial function of recombinant Pahepcidin1, and the results indicated that it possessed broad antibacterial activity against both Gram-positive bacteria (S. aureus) and Gram-negative bacteria (Edwardsiella tarda). In addition, the overexpression of Pahepcidin1 could significantly alter the transcriptional levels of key genes in the NF-κB pathway and downstream immune-related genes. In vivo validation via Vibrio parahaemolyticus challenge showed that Pahepcidin1 expression in silver pomfret liver was significantly upregulated at 3 h and peaked at 6 h, then downregulated to below the baseline from 12 h to 48 h. These results suggested that Pahepcidin1 might play an essential role in the innate immune system modulation of silver pomfret, providing valuable insights into understanding the antimicrobial immune mechanism of this species.
Hypoxic conditioning induced by CoCl enhanced the therapeutic effects of mesenchymal stem cell-derived exosomes on oxazolone-induced atopic dermatitis-like skin lesions in BALB/c mice.
Kim JW, Lee HJ, Chang PS … +2 more , Lee JM, Kim JC
Mol Immunol · 2026 Jan · PMID 41411738 · Publisher ↗
Atopic dermatitis (AD) is a chronic skin disease characterized by inflammation and disruption of the skin barrier. It is normally treated using moisturizers and steroids; however, these are palliatives and do not serve a...
Atopic dermatitis (AD) is a chronic skin disease characterized by inflammation and disruption of the skin barrier. It is normally treated using moisturizers and steroids; however, these are palliatives and do not serve as a therapy. Mesenchymal stem cells (MSCs) are tissue stem cells with immunomodulatory activities, and exosomes reflect the physiologies of producer cells. Therefore, the use of MSCs and exosomes with their immunomodulatory activities is emerging as a new method to treat AD. Here, we used cobalt chloride (CoCl) to induce hypoxic conditioning, and tested the therapeutic efficacy of exosomes derived from CoCl-treated MSCs in treating AD. In vitro, the exosomes derived from CoCl-treated MSCs increased the proliferation of HaCaT cells and decreased inflammatory cytokine levels. In the oxazolone-induced chronic AD mouse model, the exosomes derived from CoCl-treated MSCs reduced ear thickness, restored the skin barrier, and reduced immune cell infiltration and inflammatory markers. These data indicated that hypoxic conditioning induced by the CoCl treatment enhanced the therapeutic efficacy of exosomes derived from MSCs, suggesting that these exosomes can be used to alleviate the symptoms of AD. Given the current AD treatment landscape dominated by biologics and JAK inhibitors, our approach may serve as a steroid-sparing, biologic-agnostic adjunct or alternative, leveraging the safety and manufacturability of cell-free therapy.
The role of miR-3188-mediated transcriptional activation of IL-7Rα in tumor immunotherapy research.
Wan D, Liang X, Liang F … +3 more , Zhu M, Zhang C, Zhang S
Mol Immunol · 2026 Jan · PMID 41406630 · Publisher ↗
BACKGROUND: Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach for disseminated malignancies. However, ex vivo-expanded tumor-infiltrating lymphocytes (TI...
BACKGROUND: Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach for disseminated malignancies. However, ex vivo-expanded tumor-infiltrating lymphocytes (TIL) often rapidly progress to a state of functional exhaustion or suppression within the tumor microenvironment. Interleukin-7(IL-7) not only supports the survival of T-lymphocyte in vivo but also induces vigorous expansion of naïve and memory T lymphocytes in vitro. Upregulating the expression of interleukin-7 receptor alpha (IL-7Rα) helps T cells restore their responsiveness to IL-7 signaling, aids in their survival, and enables them to regain anti-tumor activity. METHODS: Firstly, we utilized databases to analyze the expression changes of CD127 in different tumor tissues, clarifying the correlation between its expression changes and patient prognosis. Subsequently, we collected clinical patient samples to validate the expression changes of CD127 in tumor-infiltrating T cells. We also simulated the tumor microenvironment through in vitro co-culture to explore the impact of tumor cells on the expression of CD127 on the surface of T cells. After then, we screened for miRNAs that are complementary to the sequence of the TATA box region in the CD127 promoter and employed a CD127 promoter driven dual-luciferase reporter system to identify the specific miRNA capable of upregulating CD127 expression. Finally, we analyzed the effects of miRNA-mediated upregulation of CD127 on T cell function. RESULTS: Bioinformatics analysis and clinical validation both confirmed decreased IL-7Rα expression in tumors. Moreover, in clinical samples, IL-7Rα and miR-3188 expression levels showed concordant changes and a positive correlation. miR-3188 can upregulate the expression level of IL-7Rα by specifically targeting the TATA-box region of CD127 promoter. Utilizing miR-3188 to upregulate IL-7Rα expression can facilitate T cell survival, promote the development of memory T cells and enhance the secondary response and tumor-killing capacity of T cells. CONCLUSION: Our findings reveal a novel mechanism of IL-7Rα regulation and propose a potential strategy to improve the persistence and functionality of T cells for ACT.
Construction of Enterococcus faecium-mediated ExoU vaccine and its protective effect in mice challenged with Pseudomonas aeruginosa.
Yang F, Yang S, Ou X … +3 more , He A, Yang X, Li W
Mol Immunol · 2026 Jan · PMID 41380468 · Publisher ↗
BACKGROUND: Pseudomonas aeruginosa (Pa) is an opportunistic pathogen and an important cause of nosocomial infections, and its antimicrobial resistance is a major therapeutic challenge. DNA vaccination is an attractive an...
BACKGROUND: Pseudomonas aeruginosa (Pa) is an opportunistic pathogen and an important cause of nosocomial infections, and its antimicrobial resistance is a major therapeutic challenge. DNA vaccination is an attractive antigen-specific immunotherapy approach. METHODS: In this study, we used the most acutely cytotoxic effector exoenzyme U (ExoU) released by Pa as the specific antigen and the safe and reliable Enterococcus faecium (Ef) as the expression vector, to construct the recombinant Ef-ExoU vaccine. The immune protection and humoral and cellular immune responses of the DNA vaccine were evaluated in mice by oral gavage. RESULTS: We found that the Ef-ExoU vaccine significantly reduced lung bacterial load and lung inflammatory cytokines (IL-6, TNF-α), probably by inducing higher levels of IgG and spleen CD4 T cell proliferation, indicating the induction of a mixed Th1 and Th2 immune response. CONCLUSIONS: This study suggests that Ef-ExoU is a promising subunit vaccine candidate and provides a new strategy for the prevention and treatment of Pa infection.
Mitochondria in pyroptosis: Mechanisms and implications.
Eldakhakhny BM, Abdulaal WH, Khan J … +7 more , Ajoolabady A, Pratico D, Bahijri S, Tuomilehto J, Borai A, Kim B, Ren J
Mol Immunol · 2026 Jan · PMID 41344083 · Publisher ↗
Pyroptosis is an inflammatory, necrotic, and lytic form of programmed cell death, involving activation of inflammasome complexes, inflammatory caspases, and the cleavage of gasdermins. Gasdermins are a large family of po...
Pyroptosis is an inflammatory, necrotic, and lytic form of programmed cell death, involving activation of inflammasome complexes, inflammatory caspases, and the cleavage of gasdermins. Gasdermins are a large family of pore-forming proteins with critical implications in key cellular processes and inflammatory disease contexts. These gasdermins subsequently oligomerize to form pores in the plasma membrane, releasing cellular contents and inflammatory mediators. Mechanistically, pyroptosis can occur via either caspase-1-dependent canonical pathway or the caspase-1-independent non-canonical pathway, both ultimately resulting in similar forms of pyroptotic cell death. While the underlying mechanisms of pyroptosis are broad and complex, certain key processes simplify the understanding of these mechanisms. One such critical process is the role of mitochondria and mitochondrial dysfunction in mediating pre-pyroptotic signaling. This review aims to provide a brief overview of the general mechanisms of pyroptosis, followed by a discussion of the latest findings on the functional and regulatory roles of mitochondria in pyroptosis. Moreover, we aimed to discuss and decipher emerging concepts such as the interaction between gasdermin D and cardiolipin, the role of mitochondrial DNA and its associated signaling pathways, as well as perspectives on the clinical relevance of these findings in conditions like sepsis, cardiotoxicity, and other diseases.
Loss of GNB2L1 promotes expansion of CD74 dendritic cells and contributes to development of diabetic foot ulcers.
Wang Y, Hang B, Liu H … +1 more , Cheng C
Mol Immunol · 2026 Jan · PMID 41344082 · Publisher ↗
Refractory diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation both locally and systemically. GNB2L1 has been reported to be associated with wound healing in diabetic rats, but the specific me...
Refractory diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation both locally and systemically. GNB2L1 has been reported to be associated with wound healing in diabetic rats, but the specific mechanism by which it acts has not been explored. scRNA-seq data from foot skin samples of three diabetic patients without DFU (non-DFU) and four diabetic patients with non-healing DFU (DFU) were downloaded from the GSE165816 dataset and analyzed. Twenty-five different cell clusters and fourteen cell types were identified, and the dendritic cell (DC) cluster was identified as a meaningful cell type. Skin wound tissues from 36 patients with DFU and 30 diabetic patients without DFU were collected. Based on gene signature analysis of the DC cluster, we identified a CD74 DC subset with a high proportion in the DFU group in clinical samples. Moreover, enrichment analysis of differentially expressed genes in the DC cluster revealed that they were mainly related to infection, immune response, and ATP synthesis. GNB2L1 was identified as the most significantly down-regulated gene, and its expression level was negatively correlated with the wound healing time in DFU patients. A full-thickness dorsal wound model in db/db mice was established, and GNB2L1 upregulation promoted wound healing in db/db mice. CD74 and CD74 DCs were isolated from blood samples of the above patients. CD74 upregulation promoted mitochondrial damage in DCs, which was reversed by GNB2L1 overexpression. In conclusion, GNB2L1 deficiency promotes CD74 dendritic cell expansion and diabetic foot ulcer development.
Fecal metabolomics in Crohn's disease reveal N-Acetylglutamine as a Th17/Treg modulator.
Han M, Dong X, Zhao R … +6 more , Hu X, Li D, Yan X, Liu Y, Du Q, Li M
Mol Immunol · 2026 Jan · PMID 41337940 · Publisher ↗
The gut microbiota is widely recognized as a key component in the pathogenesis of inflammatory bowel disease (IBD), and one of its primary modes of interaction with the host occurs via metabolites. Studies have confirmed...
The gut microbiota is widely recognized as a key component in the pathogenesis of inflammatory bowel disease (IBD), and one of its primary modes of interaction with the host occurs via metabolites. Studies have confirmed that gut microbiota dysbiosis affects immune maturation, immune homeostasis, host energy metabolism, and the maintenance of mucosal integrity. However, the specific metabolites that influence the differentiation of mucosal CD4 T cells remain insufficiently elucidated. This study aimed to identify and validate unknown metabolites capable of affecting the differentiation of CD4 T cell subsets by characterizing changes in fecal metabolites between IBD patients and non-IBD controls. Using untargeted metabolomics, we quantitatively detected a total of 1480 metabolites in positive ion mode and 1178 metabolites in negative ion mode. Regression analysis results showed that N-Acetylglutamine was significantly downregulated in IBD patients and was identified as a key differential metabolite. Further in vitro functional experiments confirmed that this metabolite could directly regulate the differentiation balance of CD4 T cells, specifically inhibiting the differentiation of pathogenic Th17 (pTh17) cells while promoting the generation of Treg. This study verifies the critical role of the metabolite N-Acetylglutamine in regulating the Treg/pTh17 cell balance, providing a theoretical basis for its potential as a therapeutic target for IBD.
Coxsackievirus B3 regulates macrophage polarization through ANXA3 to promote the development of myocarditis.
Chen Y, Liu X, Meng L … +5 more , Li B, Su Z, Jiang L, Wu Y, Zhang X
Mol Immunol · 2026 Jan · PMID 41337939 · Publisher ↗
BACKGROUND: Viral myocarditis (VMC) is a common inflammatory disease in children that is caused mainly by Coxsackievirus B3 (CVB3) infection. M1 macrophage polarization is a key pathological event in the progression of C...
BACKGROUND: Viral myocarditis (VMC) is a common inflammatory disease in children that is caused mainly by Coxsackievirus B3 (CVB3) infection. M1 macrophage polarization is a key pathological event in the progression of CVB3-induced myocarditis, and annexin 3 (ANXA3) plays an important role in the process of macrophage activation. Therefore, this study aimed to investigate the function of ANXA3 in CVB3-induced myocarditis and macrophage polarization. METHODS: CVB3-challenged mice were used to establish a CVB3-induced myocarditis model, and the polarization of RAW264.7 cells was induced by CVB3 infection. The expression of genes and proteins was detected by RT-qPCR, western blotting, immunohistochemistry, immunofluorescence, and ELISA. The pathological lesions in the cardiac tissue were detected by HE staining. Serum levels of myocardial injury markers were detected using kits. RESULTS: We found that ANXA3 expression was increased in VMC. ANXA3 knockdown hindered the progression of CVB3-induced VMC, as manifested by increased body weight, reduced inflammatory cell infiltration in the heart, and decreased serum levels of myocardial injury markers (LDH, CK, CK-MB and cTnI). ANXA3 knockdown also inhibited the M1 polarization of CVB3-infected mouse heart tissue macrophages and RAW264.7 cells in vitro and reduced the levels of the inflammatory cytokines IL-1β, IL-6, and TNF-α. In addition, CVB3 infection promoted the expression of TLR4, MyD88, and p-IκB-α in mouse heart tissues and RAW264.7 cells and the nuclear transfer of NF-κB p65 and inhibited the expression of IκB-α. Mechanistic studies revealed that CVB3 increased ANXA3 expression by activating the TLR4/MyD88 pathway, thereby promoting NF-κB p65 nuclear translocation and the subsequent M1 polarization of macrophages, eventually leading to the development of CVB3-induced myocarditis. CONCLUSION: Our study elucidated the role of ANXA3 in promoting CVB3-induced myocarditis, providing a potential intervention target for the treatment of VMC.
"Double-duty" dendritic cells in Xenopus laevis: Early vertebrate splenic APCs resemble conventional dendritic cells and limit native antigen presentation to B cells during a humoral response.
Flowers EM, Peng X, Cruz EJ … +1 more , Flajnik MF
Mol Immunol · 2026 Jan · PMID 41337938 · Full text
XL cells are class II, Ig-bearing cells found in splenic B cell follicles of the amphibian Xenopus laevis, bearing native antigen after immunization. XL cells are proposed to be myeloid cells serving the functions of bot...
XL cells are class II, Ig-bearing cells found in splenic B cell follicles of the amphibian Xenopus laevis, bearing native antigen after immunization. XL cells are proposed to be myeloid cells serving the functions of both classical dendritic cells (cDC) and mammalian follicular dendritic cells (FDC). Here, we compare the function and gene expression of XL cells with peritoneal macrophages (pMac), which are also class II/Ig-bearing cells. While pMacs were esterase-positive, adherent to plastic, and highly phagocytic, XL cells, like mammalian DC, adhered weakly to plastic, were esterase-low-to-negative, and were weakly phagocytic. Splenic red pulp macrophages, like pMacs, were esterase-positive. Both pMacs and XL cells bound to complement activated on zymosan particles. RNAseq was also done with IgY FACS-purified pMacs and XL cells. The pMac transcriptome was consistent with the classical macrophage lineage with high Mafb, myeloperoxidase, and CEBPA. In contrast, XL cells expressed cDC markers, chemokines CXCL13 and CCL19/CCL21, and the FDC marker VCAM1, consistent with their presumed function of attracting lymphocytes and presenting antigen. Mammalian FDC can present native antigen up to one year within B cell follicles, while ectotherms lack FDC but have myeloid cells that trap native antigen for unknown lengths of time. As shown previously, XL cells bear fluorescent antigen on their surface 16 days after immunization. However, we now show that antigen disappears by D30. Our data suggest that the myeloid XL cells indeed act as APC during a humoral immune response, but do not serve as an antigen depot to sustain memory B cells.
Verticinone inhibits cell growth and induces pyroptosis via regulating AKT pathway in papillary thyroid cancer.
Liu X, Liu Y
Mol Immunol · 2026 Jan · PMID 41330019 · Publisher ↗
BACKGROUND: Verticinone, an alkaloid isolated from Fritillaria, exhibits a range of biological activities. This study aims to investigate the effects of verticinone on papillary thyroid carcinoma (PTC), the most prevalen...
BACKGROUND: Verticinone, an alkaloid isolated from Fritillaria, exhibits a range of biological activities. This study aims to investigate the effects of verticinone on papillary thyroid carcinoma (PTC), the most prevalent histological type of thyroid cancer, as well as the potential mechanisms underlying these effects. METHODS: Cell counting kit-8, colony formation assay, and 5-ethynyl-2'-deoxyuridine staining were employed to evaluate the impact of verticinone on the proliferation capacity of PTC cells. Wound healing and Transwell assays were conducted to assess the effects of verticinone on the migration and invasion abilities of PTC cells. Flow cytometry was utilized to detect apoptosis in PTC cells. Western blot analysis was performed to measure the expression levels of relevant proteins. Additionally, network pharmacology analysis was conducted to identify potential targets of verticinone and thyroid carcinoma, and molecular docking was used to elucidate the targeting relationship. Finally, the effect of verticinone on tumor growth was evaluated using a xenograft tumor model. RESULTS: Verticinone inhibited the proliferation, migration, and invasion, and induced apoptosis and pyroptosis of PTC cells in a dose-dependent manner. Mechanically, verticinone targeted and inhibited protein kinase B (AKT), facilitating its degradation. AKT overexpression significantly eliminated the effect of verticinone on biological behavior of PTC cells. The results of xenograft tumor experiments demonstrated the inhibitory effect of verticinone on PTC tumor growth. CONCLUSION: Verticinone inhibited the growth of PTC cells and induced pyroptosis by regulating the AKT pathway.
Catalpol enhances mTORC1/HIF-1α/PDHK1-mediated oxidative metabolism that leads to promote the differentiation of Treg cells in RA.
Zhang Q, Wang F, Ding P … +4 more , Ge Y, Bao Y, Jiang B, Zhou L
Mol Immunol · 2026 Jan · PMID 41317620 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which regulatory T (Treg) cell dysfunction contributes to its pathogenesis, although the mechanisms regulating Treg differentiation remain unclear. In this stu...
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which regulatory T (Treg) cell dysfunction contributes to its pathogenesis, although the mechanisms regulating Treg differentiation remain unclear. In this study, the effects of Catalpol (CAT) on Treg differentiation and its underlying mechanisms were investigated using a CIA mouse model, with animals randomly allocated to CIA, CIA+CAT, and No CIA groups. Synovial pathology was assessed by HE staining, while naive CD4 T cells were differentiated into Tregs in vitro, and treated with CAT. Molecular docking predicted CAT-target interactions, and the mTORC1 activator NV5138 was used alongside CAT for intervention. Treg proportions and mitochondrial membrane potential were analyzed by flow cytometry, IL-10 levels were measured by ELISA, NAD/NADH was detected by assay kit, and mRNA expression of FOXP3, mTOR, Raptor, HIF-1α, and PDHK1 were determined by RT-qPCR, while protein expression was assessed by Western blotting. The results demonstrated that CAT alleviated joint symptoms in CIA mice, promoted Treg differentiation both in vivo and in vitro, and increased mitochondrial membrane potential, NAD/NADH and acetyl-CoA levels in Tregs. CAT also downregulated HIF-1α and PDHK1 mRNA and inhibited p-P70S6K/P70S6K, p-4EBP1/4EBP1, HIF-1α, and PDHK1 protein expression. Treatment with NV5138 was observed to reduce Treg differentiation and oxidative metabolism, effects which were reversed by CAT. These findings demonstrate that CAT promotes Treg differentiation and exerts anti-RA effects through inhibition of the mTORC1/HIF-1α/PDHK1 signaling pathway and enhancement of pyruvate aerobic oxidation.
Complement factor D is a drug target for metabolic-associated fatty liver disease.
Guo R, Li Z, Wu J … +10 more , Zhang Z, Shu J, Zhou X, Zhou W, Chen Y, Guan D, Wang Q, Shi Q, Yang H, Li G
Mol Immunol · 2025 Dec · PMID 41308544 · Publisher ↗
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Compl...
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Complement factor D (CFD), a rate-limiting serine protease in the alternative complement pathway, has been suggested to be associated with metabolic diseases in previous studies. Its inhibitor, danicopan, is primarily used for paroxysmal nocturnal hemoglobinuria (PNH), but its role in metabolic liver diseases remains underexplored. Here, we assessed the role of CFD in MAFLD and danicopan therapy using HFD mice, patient sera, and hepatocytes via CRISPR knockout and pharmacological interventions. Key findings demonstrated significant upregulation of CFD in MAFLD mice livers and patient sera. Genetic CFD ablation attenuated hepatocyte lipid deposition. Danicopan reduced intracellular triglycerides/cholesterol, improved glucose tolerance, lowered ALT, and alleviated hepatic steatosis in obese mice without weight change. Mechanistically, danicopan suppressed NF-κB signaling, inhibiting lipid-related genes (CD36/FASN/ FATP2) and inflammatory mediators (MMP12/IL-6/TNF-α). These results establish CFD as a novel MAFLD mediator, validating FDA-approved danicopan's therapeutic efficacy and translational potential. This work provides critical evidence for targeting the CFD pathway in MAFLD management.
Human cord blood mononuclear cells alleviate intestinal inflammation and barrier dysfunction by regulating gut metabolites and Th17/Treg balance.
Lyu L, Ma Y, Sun X … +7 more , Luo M, Wang Z, Fang L, Li W, Chen Y, Liu S, Jia X
Mol Immunol · 2025 Dec · PMID 41297113 · Publisher ↗
BACKGROUND: Cord blood mononuclear cells (CB-MNCs) are a potential alternative therapy for inflammatory bowel disease (IBD). Gut metabolites, T helper 17 (Th17) and regulatory T (Treg) cells are crucial for intestinal he...
BACKGROUND: Cord blood mononuclear cells (CB-MNCs) are a potential alternative therapy for inflammatory bowel disease (IBD). Gut metabolites, T helper 17 (Th17) and regulatory T (Treg) cells are crucial for intestinal hemeostasis and recovery. However, the role of CB-MNCs in modulating IBD, gut metabolites and the Th17/Treg balance remains unclear. METHODS: In this study, dextran sodium sulfate (DSS) was used to induce acute colitis in male C57BL/6 J mice, followed by treatment with CB-MNCs, umbilical cord-derived mesenchymal stem cells (UC-MSCs), or mesalazine. The severity of colitis was assessed daily using the disease activity index (DAI), and feces were collected for metabolomic analysis. Upon sacrifice, the colons, mesenteric lymph nodes (MLNs) and spleens of the mice were preserved for further study. RESULTS: Our findings demonstrated that compared with UC-MSCs and mesalazine, CB-MNCs treatment had superior efficacy in improving clinical symptoms, tissue repair, promoting intestinal regeneration and integrity. While CB-MNCs were equivalent to UC-MSCs and mesalazine in terms of preserving colon length and anti-inflammatory activity. At the molecular level, CB-MNCs exhibited unique and powerful effects. CB-MNCs were found to significantly increase the abundance of cortisol, corticosterone, and several metabolites with anti-inflammatory and antioxidant activities in the feces of colitis mice. CB-MNCs were also more effective than UC-MSCs and mesalazine at maintaining Th17/Treg balance than UC-MSC and mesalazine in colitis mice. CONCLUSIONS: The intravenous injection of CB-MNCs can alleviate intestinal inflammation and barrier dysfunction by modulating gut metabolites and the Th17/Treg balance. Therefore, CB-MNCs be a promising treatment for IBD.
NSUN2-mediated m⁵C methylation of HSPB1 mRNA suppresses inflammation and ferroptosis in ischemic stroke via activating the NRF2/HO-1/NQO-1 pathway.
Gao G, Zhang B, Liu N … +3 more , Liu N, Zhang Y, Du H
Mol Immunol · 2025 Dec · PMID 41274106 · Publisher ↗
Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic...
Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic mark involved in various pathological processes, yet its role in IS remains unclear. This study aimed to investigate the role of m5C modification in IS and its underlying mechanisms. In vitro, human brain microvascular endothelial cells (HBMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), while in vivo, a transient middle cerebral artery occlusion (tMCAO) mouse model was established. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of NSUN2 and heat shock protein family B member 1 (HSPB1). The contents of pro-inflammatory cytokines and ferroptosis-related indicators were measured using enzyme-linked immunosorbent assay and commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1)/NAD(P)H quinone dehydrogenase 1 (NQO-1) pathway proteins was detected by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were performed to assess the interaction between NSUN2 and HSPB1. Results showed that NSUN2 was downregulated in OGD/R-treated HBMECs and tMCAO mice. Furthermore, NSUN2 overexpression mitigated OGD/R-induced inflammation and ferroptosis. Mechanistically, NSUN2 mediated m5C methylation at site 621 in HSPB1 mRNA, enhancing its stability. Knockdown of HSPB1 abolished the protective effects of NSUN2, exacerbating inflammation and ferroptosis in OGD/R-treated HBMECs. Further investigations revealed that the NSUN2/HSPB1 axis exerted its protective role by activating the NRF2/HO-1/NQO-1 pathway. Inhibition of this pathway reversed the beneficial effects of HSPB1 overexpression. In tMCAO mice, NSUN2 overexpression reduced cerebral infarct volume, improved antioxidant capacity, and activated the NRF2/HO-1/NQO-1 pathway. In conclusion, NSUN2-mediated m⁵C methylation stabilized HSPB1 and activated the NRF2/HO-1/NQO-1 pathway, thereby mitigating inflammation and ferroptosis in IS. Targeting the NSUN2/HSPB1 axis may represent a novel therapeutic strategy for IS.
Astragalus polysaccharide promotes CD8 + T cell activity by downregulating Tim-3 to potentiate antitumor immunity.
Liu P, Wang S, Bin Y … +7 more , Xin Z, Yang H, Zhang T, Xie W, Wang K, Yin W, Zhang H
Mol Immunol · 2025 Dec · PMID 41270296 · Publisher ↗
It is well known that Astragalus polysaccharide (APS) exerts potent antitumor effects by enhancing T cell cytotoxicity via the PD-1/PD-L1 axis. However, whether APS can also modulate T cell activity via alternative check...
It is well known that Astragalus polysaccharide (APS) exerts potent antitumor effects by enhancing T cell cytotoxicity via the PD-1/PD-L1 axis. However, whether APS can also modulate T cell activity via alternative checkpoint molecules remains unclear. Here, we addressed this question using complementary in vitro and in vivo approaches. In vitro, APS reduced the Tim-3 + cell population among human PBMCs. Further analysis revealed that APS specifically affected only the proportion of Tim-3 +CD8 + T cells. Along with the decreased proportion of Tim-3 + cells, CD8 + T cell immune activity was enhanced, as shown by increased expression of the early activation molecule CD69, increased secretion of GZMB, and enhanced capacity to kill human lung cancer cells. The results of transcriptome sequencing suggested that the APS-induced downregulation of Tim-3 might be related to the regulation of the transcription factor RORB. Experiments in an in vivo B16-F10 melanoma model revealed that APS enhanced T cell function by reducing the number of tumor-infiltrating Tim-3 + T cells, consequently suppressing tumor cell proliferation in mice. Collectively, our findings demonstrate that APS reduces the Tim-3 +CD8 + T cell population among PBMCs and enhances T cell cytotoxicity, providing a novel theoretical foundation for explaining the mechanism underlying APS immunomodulation.
Investigating the role of nuclear factor erythroid 2-related factor 2 pathway on T cell & endothelial cell-based in vitro autoimmune disease model.
Özeken Hİ, Sağraç D, Kırbaş OK … +2 more , Taşlı PN, Şahin F
Mol Immunol · 2025 Dec · PMID 41240478 · Publisher ↗
Autoimmune disease is a complex condition where the immune system mistakenly attacks healthy tissues and affects millions around the world. Although there is no definitive cure or effective treatment, targeting the inter...
Autoimmune disease is a complex condition where the immune system mistakenly attacks healthy tissues and affects millions around the world. Although there is no definitive cure or effective treatment, targeting the interaction between leukocytes and vascular endothelium presents a promising strategy for reducing excessive immune infiltration. Among strategies, combating oxidative stress and inflammation by activating antioxidant and anti-inflammatory genes is the best solution to decrease immune filtration. Nuclear-factor-erythroid 2-related factor-2 (NRF2) is a key player regulating oxidative stress and inflammation. This study investigates the anti-inflammatory impacts of the NRF2 pathway on the activated T cells that nonspecifically induce endothelial inflammation. To explore this, the NRF2 pathway in Human Umbilical Vein Endothelial Cells (HUVEC) was induced by using two approaches: NRF2 gene overexpression through the lentiviral systems (NRF2OE) and synthetic inducer, tert-butyl hydroquinone (TBHQ). These types of conditioned cells were co-cultured with activated Jurkat T cells to evaluate any regulatory effects of the NRF2 protein. Here, we observed that NRF2OE HUVEC cells induced a possible phenotypic shift from pro-inflammatory Th1 cells to anti-inflammatory Treg cells through upregulation of IL10 expression and downregulation of IL2 and IL2RA. This shift may demonstrate that NRF2 and its downstream pathway may help regulate immune responses by enhancing immune tolerance and reducing inflammation. Overall, these findings highlight the NRF2 pathway as a powerful modulator of endothelial inflammation and indicate its potential as a valuable therapeutic target for treating autoimmune diseases.
Differential impact of porcine reproductive and respiratory virus and swine Influenza A virus infections on respiratory Lymph Nodes B cells and macrophages.
Hervet C, Perrin A, Renson P … +8 more , Deblanc C, Muñoz M, Meurens F, Argilaguet J, Simon G, Bourry O, Maisonnasse P, Bertho N
Mol Immunol · 2025 Dec · PMID 41218477 · Publisher ↗
Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) has a profound impact on the swine industry due to its ability to persist in infected animals. The PRRSV family exhibits considerable genetic variability, with...
Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) has a profound impact on the swine industry due to its ability to persist in infected animals. The PRRSV family exhibits considerable genetic variability, with PRRSV-1 and PRRSV-2 now classified as two distinct species (Betaarterivirus suid 1 and 2). Interestingly, both species - and their corresponding attenuated vaccine strains - can persist for months, in part by delaying the appearance of neutralizing antibodies. Leveraging recently developed tools for in-depth analysis of the previously poorly characterized porcine inverted lymph node (LN), we investigated early events in LN B cell maturation during PRRSV-1 infection and compared them to those induced by acute swine influenza A virus infection. We highlighted PRRSV-specific mechanisms, including PD-L1 upregulation in efferent macrophages, the presence of extrafollicular centrocytes, and the influx of inflammatory monocytes/macrophages. These findings are consistent with previous observations in PRRSV-2 infections and may therefore reflect conserved immune evasion mechanisms across PRRSV strains.
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