Molecular Immunology[JOURNAL]
Sun
200 papers
Preparation of African swine fever virus (ASFV) p30 monoclonal antibodies and identification of novel antigenic epitopes.
Zhang J, Zhang K, Sun S … +9 more , Deng D, He P, Lv H, Jiang S, Zheng W, Chen N, Gu J, Bai J, Zhu J
Mol Immunol · 2025 Sep · PMID 40669107 · Publisher ↗
African swine fever (ASF) is a highly infectious disease caused by African swine fever virus (ASFV), with a mortality rate of up to 100 % for highly virulent strains. The ASFV p30 protein is encoded by the early transcri...
African swine fever (ASF) is a highly infectious disease caused by African swine fever virus (ASFV), with a mortality rate of up to 100 % for highly virulent strains. The ASFV p30 protein is encoded by the early transcriptional gene CP204L. As one of the structural proteins of ASFV, p30 is an ideal diagnostic antigen for ASF. Here, we first generated three monoclonal antibodies (mAbs) specific for p30 from immunized BALB/c mice via cell fusion, which were successfully applied in ELISA, Western blotting, and immunofluorescence assay. Second, two novel antigenic epitopes, TIYGTPLKE and ETNECTSSFET of p30 were identified using Western blotting with the three p30 mAbs. The two epitopes identified were highly conserved across genotypes I and/or II ASFVs. Third, an indirect ELISA based on epitope peptides of p30 was established to effectively detect antibodies during ASFV infection.
MSC-EVs alleviate sepsis-induced acute lung injury through inhibiting NET-triggered damage to adherens junctions of endothelial cells.
Shao Y, Wu D, Miao C … +1 more , Zhang H
Mol Immunol · 2025 Sep · PMID 40664021 · Publisher ↗
Neutrophil extracellular traps (NETs) play a crucial role in the progression of sepsis-induced acute lung injury (SI-ALI). Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) are considered to have poten...
Neutrophil extracellular traps (NETs) play a crucial role in the progression of sepsis-induced acute lung injury (SI-ALI). Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) are considered to have potential therapeutic effects on SI-ALI. Nevertheless, a comprehensive understanding of the precise mechanism is currently lacking. This study intends to illustrate the therapeutic mechanisms of MSC-EVs against NET-mediated SI-ALI. In vivo and in vitro experiments demonstrate that NETs reduced the expression of VE-cadherin through calpain 1/2 activation, thereby impairing endothelial barrier function and exacerbating the pathogenesis of SI-ALI. MSC-EVs were found to alleviate SI-ALI by reducing the formation of NETs. Additionally, MSC-EVs inhibited NET generation by shifting NETosis to apoptosis through the ROS/AKT pathway. This study delineates the pathogenic role of NET-induced endothelial injury in SI-ALI and promotes MSC-EVs as a novel therapeutic approach for this disease.
CFH nonsense mutation-mediated pregnancy-associated atypical hemolytic uremic syndrome: Case report.
Hu C, Zhang P, Xu Q … +5 more , Qin R, Chen W, Shi Z, Chen P, Xu M
Mol Immunol · 2025 Sep · PMID 40651090 · Publisher ↗
Pregnancy-associated hemolytic uremic syndrome (P-aHUS) is characterized by microvascular hemolytic anemia, thrombocytopenia, and acute organ damage, particularly acute kidney injury, occurring during pregnancy or in the...
Pregnancy-associated hemolytic uremic syndrome (P-aHUS) is characterized by microvascular hemolytic anemia, thrombocytopenia, and acute organ damage, particularly acute kidney injury, occurring during pregnancy or in the postpartum period. This rare disease has been associated with mutations in genes that regulate the complement system in most reported cases. This article introduces a 38-year-old maternal, who gave birth again after 13 years. Approximately four days post-cesarean section, she developed severe anemia, thrombocytopenia, renal impairment, and abnormal liver function, prompting urgent symptomatic treatment by the doctor. Subsequent detections revealed decreased complement C3 levels, a negative result for the ADAMTS13 inhibitory antibody, and a negative stool culture for bacterial fungi. The diagnosis of P-aHUS was confirmed, and the condition was successfully managed with complement blockade therapy using Eculizumab. Genetic sequencing of the complement factor H (CFH) gene revealed the c.3643 C > T mutation (p.Arg1215*), indicating the presence of rare CFH gene variants that may contribute to the patient's condition. These findings elucidate the clinical manifestations and treatment responses associated with the rare disease P-aHUS in relation to specific gene mutations. We underscore the significance of genetic testing for accurate diagnosis and personalized treatment, offering new insights and evidence for the future clinical management and research of similar cases.
Knockdown of FSTL1 attenuates sepsis-induced acute lung injury by inhibiting inflammation and ferroptosis.
Zhou X, Gao B, Li K … +4 more , Fu H, Hao Y, Lan A, Zhou F
Mol Immunol · 2025 Aug · PMID 40617172 · Publisher ↗
Sepsis is a life-threatening condition characterized by high morbidity and mortality, with acute lung injury being the earliest and most severe complication. The damage to pulmonary microvascular endothelial cells (HPMEC...
Sepsis is a life-threatening condition characterized by high morbidity and mortality, with acute lung injury being the earliest and most severe complication. The damage to pulmonary microvascular endothelial cells (HPMECs) resulting from excessive inflammation plays a critical role in sepsis-induced acute lung injury (si-ALI). This study aimed to elucidate the role of Follistatin-like protein 1 (FSTL1) in si-ALI and its underlying pathophysiological mechanisms. We established an in vitro model of HPMECs stimulated by lipopolysaccharide (LPS), revealing a significant upregulation of FSTL1 at both mRNA and protein levels. Knockdown of FSTL1 mitigated inflammation by inhibiting the secretion of interleukin-1β (IL-1β) and interleukin-6 (IL-6), reducing reactive oxygen species (ROS) production, malondialdehyde (MDA) and ferrous ion (Fe) levels, while simultaneously increasing glutathione (GSH) levels. Moreover, western blot showed that the knockdown of FSTL1 effectively suppresses cellular ferroptosis through the upregulation of SLC7A11, GPX4, and FTH. Conversely, FSTL1 overexpression exacerbated inflammation and ferroptosis, an effect reversible partly by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Furthermore, utilizing cecal ligation and puncture (CLP) method to establish sepsis mice model demonstrated that silencing of FSTL1 alleviated lung tissue damage associated with sepsis-induced pulmonary injury while inhibiting IL-1β and IL-6, ROS production, and ferroptosis. In conclusion, our findings indicated that knockdown of FSTL1 significantly improved si-ALI both in vitro and in vivo, suggesting it as a potential therapeutic target for managing sepsis-induced acute lung injury.
Gut microbiota-derived Proline-Leucine dipeptide aggravated sepsis-induced acute lung injury via activating Nod2/NF-κB signaling pathway.
Yang L, He S, Wei A … +7 more , Wang X, He L, Cui L, Zhang S, Zhong C, Zhuo Y, Wang X
Mol Immunol · 2025 Aug · PMID 40614662 · Publisher ↗
OBJECTIVE: Gut microbiota-derived metabolites can modulate lung tissue damage via the gut-lung axis. This study aimed to delineate the alterations in gut microbiota and metabolites associated with sepsis and elucidate th...
OBJECTIVE: Gut microbiota-derived metabolites can modulate lung tissue damage via the gut-lung axis. This study aimed to delineate the alterations in gut microbiota and metabolites associated with sepsis and elucidate their role in potentiating lung tissue damage. METHODS: We employed 16S rDNA sequencing and non-targeted metabolomics to assess the changes in gut microbiota and metabolites, utilizing a rat model of sepsis. Furthermore, we investigated the contributions of the gut microbiota-derived Proline-Leucine (Pro-Leu) dipeptide and lipopolysaccharide (LPS) in driving lung inflammation, utilizing both mouse models and MH-S cells. RESULTS: Our findings indicate that sepsis significantly diminished gut microbiota diversity and markedly increased the relative abundance of Bacteroidetes and Escherichia-Shigella, as well as the metabolite Pro-Leu. Notably, Pro-Leu levels correlated with changes in bacterial communities. Additionally, Pro-Leu effectively exacerbated sepsis-induced lung damage. Both Pro-Leu and LPS notably enhanced pro-inflammatory cytokine production (TNF-α, IL-6, and IL-1β) by up-regulating C/EBP-β, p-NF-κB, and NOD2 in lung tissues and MH-S cells. CONCLUSIONS: Our findings suggest that Pro-Leu and LPS can synergistically intensify lung inflammation by activating the C/EBP-β/NOD2/NF-κB signaling pathways. IMPORTANCE: Our findings indicate that sepsis can lead to a disruption of the gut microbiota, an increase in pathogenic bacteria such as Escherichia-Shigella and Bacteroides, and that metabolites derived from the gut microbiota can modulate the lung inflammatory response through the gut-lung axis. Notably, Pro-Leu, a metabolite produced by the gut microbiota, was found to aggravate sepsis-induced ALI by activating the C/EBP-β/NOD2/NF-κB signaling pathways.
Genetics and humoral responses of the immune system to Aspergillus fumigatus.
Sanya DRA, Jayachandran K, Onésime D
Mol Immunol · 2025 Aug · PMID 40609370 · Publisher ↗
Due to the increasing incidence of invasive aspergillosis (IA) caused by the opportunistic fungal pathogen Aspergillus fumigatus, coupled with rising antifungal resistance and high mortality rates globally, novel antifun...
Due to the increasing incidence of invasive aspergillosis (IA) caused by the opportunistic fungal pathogen Aspergillus fumigatus, coupled with rising antifungal resistance and high mortality rates globally, novel antifungal development is a critical priority for reducing disease burden. The opportunistic fungus Aspergillus fumigatus, prevalent in the environment alongside other fungi, infects immunocompromised individuals with weakened immune systems. The pathogen can cause severe diseases with fatal outcomes. Risk factors contributing to the severity of A. fumigatus-associated diseases have been identified, and the efficacy and molecular targets of antifungal drugs have been documented. Here, we describe specific interactions between the human immune system and the airborne pathogen A. fumigatus, emphasizing how co-infections influence virulence and disease progression. We reported A. fumigatus cell wall components, such as β-glucans, that mediate interactions with the host immune system, acting as virulence factors driving significant morbidity and mortality. We also discovered compounds, biomarkers, and non-coding RNAs with potential for immunotherapy, suitable for applications in targeted antifungal therapy, vaccine development, and diagnostics..
NME4: A novel metabolic-associated biomarker for prognosis prediction and immunotherapy response evaluation in clear cell renal cell carcinoma.
Cheng S, Lin Q, Chen K … +6 more , Wang J, Peng H, Huang Y, Mao X, Lu J, Zhong C
Mol Immunol · 2025 Aug · PMID 40602220 · Publisher ↗
BACKGROUND: The incidence of renal cell carcinoma (RCC) remains high and continues to rise annually, with the clear cell subtype accounting for the majority of cases histologically. While immunotherapy has partially impr...
BACKGROUND: The incidence of renal cell carcinoma (RCC) remains high and continues to rise annually, with the clear cell subtype accounting for the majority of cases histologically. While immunotherapy has partially improved the 5-year relative survival rate, response rates vary due to individual heterogeneity, and the overall prognosis remains poor, particularly for high-stage patients. There is an urgent need to identify novel biomarkers for predicting patient prognosis and immunotherapy efficacy to enable personalized treatment. METHODS: Univariate and multivariate Cox regression analysis were employed to validate the prognostic value of NME4 in clear cell renal cell carcinoma (ccRCC) across four cohorts, followed by functional enrichment analysis to elucidate its biological functions. Cellular experiments were conducted to verify NME4's role in ccRCC proliferation and migration. Furthermore, the TIDE (Tumor Immune Dysfunction and Exclusion) algorithm and external datasets were utilized to investigate NME4's predictive capacity for immunotherapy response, while using the 'IOBR' package to analyze the relationship between NME4 and ccRCC immune microenvironment. Finally, somatic mutation and copy number variation analysis provided multi-omics insights into NME4's molecular mechanisms in ccRCC. RESULTS: Our study determined the predictive ability of NME4 for ccRCC patient prognosis, and patients with high NME4 expression had worse OS and PFI. Functional enrichment analysis revealed the biological functions of NME4, indicating its involvement in the reprogramming of multiple metabolic pathways. Cellular experiments showed that NME4 promoted the proliferation and migration of ccRCC. The TIDE algorithm and external datasets indicated that low NME4 expression predicts better responses to immunotherapy. Additionally, significant differences were observed between NME4 expression subgroups in multi-omics data analysis based on somatic mutation and copy number variation. CONCLUSION: In this study, we validated NME4's prognostic predictive capacity for ccRCC patients. Meanwhile, NME4 is expected to be a molecular marker to guide the precise application of immunotherapy in clinical practice.
Linker histone H1.3 promotes IFN-β production targeting MDA5 signaling to inhibit EMCV infection.
Li H, Dou X, Wang N … +7 more , Lian R, Li S, Xie J, Li X, Yang Y, Wen Y, Feng R
Mol Immunol · 2025 Aug · PMID 40580683 · Publisher ↗
Multiple core histones play pivotal roles in viral infection process, as evidenced in influenza virus and other viruses. Recent findings indicate that linker histone H1.2 regulates the interferon signaling pathway to mod...
Multiple core histones play pivotal roles in viral infection process, as evidenced in influenza virus and other viruses. Recent findings indicate that linker histone H1.2 regulates the interferon signaling pathway to modulate influenza and EMCV infections, while H1.3 may also play a role in EMCV infection. In this study, we initially demonstrated that overexpression of H1.3 markedly suppressed the EMCV replication and proliferation. Conversely, knockdown of H1.3 expression led to an upregulation of EMCV replication and proliferation. Additionally, we observed a significant enhancement of EMCV-induced type I IFN production in Myc-H1.3 expressing cells. Our further exploration revealed that H1.3 upregulated the expression of MDA5 and enhanced the phosphorylation of TBK1 and IRF3 during EMCV infection, with opposite effects observed in H1.3 knockdown cells. Subsequently, we confirmed the interaction between H1.3 and MAVS, as well as IRF3, using both endogenous and exogenous Co-IP assays. Furthermore, we demonstrated that H1.3 promoted IRF3 phosphorylation and its nuclear translocation in EMCV-infected A549 cells. Notably, the N-terminal domain of H1.3 may play a crucial role in regulating the IFN-β signaling pathway to inhibit EMCV replication. Finally, we observed that EMCV infection upregulated the phosphorylation of H1.3, which may correlate with increased transcriptional expression of genes such as IFN-β. In summary, our findings address the gap in understanding the involvement of H1.3 in viral infection and elucidate the mechanism by which H1.3 negatively regulates EMCV replication. These findings may provide new insights into potential antiviral targets.
Network pharmacology and in vivo investigation of the growth and immunity-enhancing mechanisms of Tetramethylpyrazine (TMP) in Litopenaeus vannamei.
Liu R, Jing F, Chen Z … +4 more , Lu M, Yu X, Li Y, Pan L
Mol Immunol · 2025 Aug · PMID 40578072 · Publisher ↗
In this study, the shrimp (L. vannamei, 0.89 ± 0.04 g) were fed formulated diets supplemented with Tetramethylpyrazine for six weeks under routine aquaculture conditions, followed by a three-day challenge with White Spot...
In this study, the shrimp (L. vannamei, 0.89 ± 0.04 g) were fed formulated diets supplemented with Tetramethylpyrazine for six weeks under routine aquaculture conditions, followed by a three-day challenge with White Spot Syndrome Virus (WSSV). The results showed that dietary TMP supplementation significantly improved the specific growth rate and weight gain rate, while reducing the feed conversion ratio. During the viral challenge, the immune protection rate of shrimp was significantly enhanced (P < 0.05). Further analysis using network pharmacology, molecular docking, and quantitative real-time PCR demonstrated that TMP exhibited strong binding affinities with hypoxia-inducible factor 1-alpha (HIF1A), prostaglandin synthase (PTGSH2), and nuclear transcription factors (Relish and Dorsal). At the transcriptional level, TMP significantly inhibited the expression of HIF1A and sterol regulatory element-binding protein (SREBP), while upregulating adiponectin receptor (AdipoR) expression. TMP also promoted lipid catabolismand cholesterol efflux-related genes, while downregulating lipid synthesis genes. Moreover, TMP enhanced the expression of arachidonic acid pathway-related genes and antioxidant enzymes, leading to reduced levels of malondialdehyde (MDA) and blood lipids. Regarding immune stimulation, TMP activated the NF-κB (Dorsal, Relish) signaling pathway, upregulated the expression of antimicrobial peptides, and reduced inflammatory cytokine levels. Under WSSV infection, TMP suppressed viral replication by downregulating HIF1A and VEGF expression (P < 0.05), suggesting that TMP exerts its antiviral effect. High-throughput sequencing of the intestinal microbiota indicated that TMP supplementation increased the abundance of beneficial bacteria and decreased the abundance of harmful bacteria, thereby improving intestinal mucosal barrier function. In conclusion, considering both growth performance and physiological health, we recommend an optimal TMP supplementation level of 150 mg/kg in shrimp feed.
Cellular interactions in maintaining an inflammatory microenvironment in rheumatoid arthritis.
Ganeshalingam S, Wilson NJ, Ciciriello S … +2 more , Antonipillai J, Achuthan AA
Mol Immunol · 2025 Aug · PMID 40561673 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and progressive joint destruction, driven by complex pathogenic mechanisms. Aberrant activation of various cellular compo...
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and progressive joint destruction, driven by complex pathogenic mechanisms. Aberrant activation of various cellular components and their dynamic interactions contribute significantly to the onset and progression of RA. Key cell types involved include non-immune cells, such as fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS), innate immune cells (neutrophils, dendritic cells, and macrophages) and adaptive immune cells (B cells and T cells). These cells collectively release high levels of proinflammatory cytokines (e.g., TNF, IL-1β, IL-6, IL-17, GM-CSF, and lymphotoxins), chemokines (e.g., CCL17, CCL22, CXCL8 and CXCL10), growth factors (e.g., PDGF, and TGF-β), pro-angiogenic factors (e.g., VEGF and FGF), matrix metalloproteinases (e.g., MMP2 and MMP9), and autoantibodies (e.g., RF and ACPA) that collectively contribute to maintaining an inflammatory microenvironment in RA joints. These molecular mediators recruit and activate distinct cellular subsets that perpetuate inflammation. This review provides an overview of the major cellular subpopulations and their intricate interactions within the RA synovium that ultimately lead to sustained synovial inflammation, bone erosion and cartilage damage. In addition, some insights into the potential disruption of such cellular activations and interactions as therapeutic strategies to achieve better treatment outcomes are also provided.
The effects of tolerogenic dendritic cells on the TLR4/MyD88/NF-κB signaling pathway in rats with collagen-induced arthritis.
Li H, Zheng T, Wan X … +5 more , Yuan R, Bao L, Long T, Zhou Y, Jiang H
Mol Immunol · 2025 Aug · PMID 40561672 · Publisher ↗
OBJECTIVE: Rheumatoid arthritis (RA) is a common inflammatory autoimmune disease. Previous studies have emphasized tolerogenic dendritic cells(tolDCs) could attenuate inflammatory lesions by inducing specific immune tole...
OBJECTIVE: Rheumatoid arthritis (RA) is a common inflammatory autoimmune disease. Previous studies have emphasized tolerogenic dendritic cells(tolDCs) could attenuate inflammatory lesions by inducing specific immune tolerance in RA animal models, but the mechanism still needs further investigation. This study focused on revealing the effects of tolDCs on the TLR4/MyD88/NF-κB signaling pathway that mediates inflammation. METHODS: Bone marrow-derived tolDCs were induced by IL-4, GM-CSF and NF-κB Oligonucleotide Decoys. The DC-specific molecule OX-62 and co-stimulatory molecules CD80 and CD86 on the surface of tolDCs were detected by flow cytometry. Joint damage was assessed by H&E, Safranine O-fast green staining and tartrate-resistant acid phosphase (TRAP) staining, and the histological change of spleen tissue was also evaluated by H&E staining. Immunohistochemistry (IHC) was performed to detect key proteins of TLR4/MyD88/NF-κB signaling pathway of synovium, cartilage, and bone tissues of ankle joints respectively. Immunofluorescence (IF) was performed to observe NF-κB p65 nuclear translocation and subcellular localization of phosphorylated NF-κB p65 (p-NF-κB p65). RESULTS: The intervention of tolDCs showed a significant reduction in joint inflammation and destruction in CIA rats. Moreover, tolDCs suppressed the hyperactivation of the TLR4/MyD88/NF-κB signaling pathway of the cells in synovium, cartilage and bone tissues of ankle joints in CIA rats. CONCLUSIONS: TolDCs may exert therapeutic effects on CIA rats by alleviating the inflammation through inhibiting the hyperactivation of the TLR4/MyD88/NF-κB signaling pathway.
CD137 might be a pivotal regulator of Th1/Th17-driven autoimmunity and B-cell hyperactivity in hyperthyroidism.
Li S, Li K, Li J … +2 more , Wang Y, Shi Q
Mol Immunol · 2025 Aug · PMID 40541003 · Publisher ↗
OBJECTIVE: This study aims to investigate the impact of antithyroid drug (ATD) intervention on the expression levels of CD137, IFN-γ, and IL-17 in plasma cytokines, chemokines, and peripheral blood mononuclear cells (PBM...
OBJECTIVE: This study aims to investigate the impact of antithyroid drug (ATD) intervention on the expression levels of CD137, IFN-γ, and IL-17 in plasma cytokines, chemokines, and peripheral blood mononuclear cells (PBMCs) of hyperthyroid patients, compared to healthy controls. The goal is to elucidate the involvement of Th cell immune balance, as well as cellular and humoral immunity, in the pathogenesis of hyperthyroidism. METHODS: Eighty-one hyperthyroidism patients diagnosed between April 2021 and April 2022 were initially included in the study. Twenty-five patients underwent antithyroid drug (ATD) therapy and were subsequently categorized into the post-intervention group, with an average treatment duration of 129.84 days. Moreover, eighty-three healthy individuals were enlisted as controls. Plasma cytokine concentrations, soluble CD137 (sCD137) levels, and CD137 expression on T and B lymphocytes were evaluated through liquid-phase microarrays, enzyme-linked immunosorbent assay (ELISA), and flow cytometry techniques. RESULTS: 1. Compared to the normal control group, the pre-intervention group exhibited elevated peripheral plasma levels of IFN-γ, TNF-α, IL-7, IL-8, IL-17A, MCP-1, MIP-1β, and IL-10. Following ATD intervention, the post-intervention group showed increased peripheral plasma levels of IL-1β, TNF-α, IL-4, and MIP-1β relative to the normal control group. Furthermore, levels of TNF-α, MCP-1, IL-13, and IL-10 were higher in the pre-intervention group than in the post-intervention group (P < 0.05). 2. The percentage of CD19 + B cells in peripheral blood mononuclear cells (PBMCs) was higher in the pre-intervention group than in the normal control group (P < 0.05). 3. The percentages of CD4 +CD137 + T cells, CD8 +CD137 + T cells, and CD19 +CD137 + B cells in PBMCs were greater in the pre-intervention group than in the normal control group (P < 0.05). 4. The concentration of sCD137 in peripheral plasma was higher in the pre-intervention group than in the normal control group (P < 0.05). 5. Levels of IFN-γ and IL-17A secretion by CD4 + T cells, as well as IFN-γ secretion by CD8 + T cells in stimulated PBMCs, were higher in the pre-intervention group than in the normal control group (P < 0.05). CONCLUSION: Hyperthyroidism is marked by immune dysregulation, evident in altered Th1/Th2/Th17 cytokine expression and elevated CD137 activity. CD137 emerges as a promising biomarker for immune function and a potential therapeutic target.
Agmatine ameliorates sepsis-related intestinal injury via the AhR-STAT3-IL-10 pathway.
Pan J, Gan L, Chen Y … +4 more , Zhong L, Deng H, Huang L, Liang H
Mol Immunol · 2025 Aug · PMID 40516501 · Publisher ↗
BACKGROUND: Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. Ho...
BACKGROUND: Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism. METHODS: We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-α induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot. RESULTS: The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1β, IL-6, and TNF-α, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway. DISCUSSION AND CONCLUSION: AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3-IL-10 pathway, thereby offering theoretical basis for clinical treatment of sepsis.
Klotho promotes bone formation in rheumatoid arthritis-associated osteoporosis by modulating the Fgf23/Fgfr1/NF-κB pathway and inhibiting ferroptosis.
Ji L, Kong R, Yu Y … +3 more , Wan W, Zhao D, Gao J
Mol Immunol · 2025 Aug · PMID 40513341 · Publisher ↗
AIMS: Rheumatoid arthritis (RA) frequently leads to osteoporosis (OP) and increased fracture risk. The protein Klotho plays a recognized role in bone metabolism, yet its specific function in RA-associated osteoporosis (R...
AIMS: Rheumatoid arthritis (RA) frequently leads to osteoporosis (OP) and increased fracture risk. The protein Klotho plays a recognized role in bone metabolism, yet its specific function in RA-associated osteoporosis (RA-OP) remains incompletely understood. This study investigated the molecular mechanisms by which Klotho maintains bone homeostasis in RA-OP patients. METHODS AND ANALYSIS: We quantified Klotho levels in RA-OP patients and healthy controls and then conducted in vitro experiments using mouse embryonic osteoblast precursor cell line (MC3T3-E1) preosteoblastic cells to examine Klotho's effects on osteogenic differentiation and ferroptosis. We assessed osteogenic differentiation through runt-related transcription factor 2 (Runx2), collagen type i alpha 1 chain (Col1a1), and osteocalcin (Ocn) expression, while ferroptosis regulation was evaluated via glutathione peroxidase 4 (Gpx4) and Acyl-CoA synthetase long-chain family member 4 (Acsl4) expression. The interaction between fibroblast growth factor 23 (Fgf23) and fibroblast growth factor receptor 1 (Fgfr1) was analyzed using coimmunoprecipitation assays, with Fgf23's role examined through knockdown and overexpression experiments. RESULTS: Results showed RA-OP patients had significantly reduced Klotho levels compared to controls. Klotho overexpression in MC3T3-E1 cells enhanced osteogenic differentiation and protected against ferroptosis by upregulating Gpx4. Mechanistically, Klotho facilitated Fgf23-Fgfr1 interaction and repressed nuclear factor κ (NF-κB) signaling. CONCLUSION: Our findings demonstrate that Klotho mediates osteogenic action through the Fgf23/Fgfr1-NF-κB pathway while simultaneously protecting osteoblasts from ferroptosis, advancing our understanding of RA-OP pathophysiology and identifying Klotho as a promising therapeutic target for preventing RA-related bone loss.
DNA vaccination combined with immune checkpoint inhibition eradicates tumors, inducing life-long immunity against breast cancer in mice.
Domínguez-Romero AN, Esquivel-García CA, Martínez-Cortés F … +7 more , Martínez-Zarco BA, Odales J, Abraham-Ruiz S, Maruri J, Villegas-Ruiz V, Gevorkian G, Manoutcharian K
Mol Immunol · 2025 Aug · PMID 40483788 · Publisher ↗
The employment of cancer vaccines as stand-alone or combined therapies has not yet reached clinically relevant endpoints in large clinical trials in the vast majority of patients, and there is a clear need for novel idea...
The employment of cancer vaccines as stand-alone or combined therapies has not yet reached clinically relevant endpoints in large clinical trials in the vast majority of patients, and there is a clear need for novel ideas and qualitatively new vaccine design approaches. In this study, we used a novel Variable Epitope Library (VEL) vaccine strategy, which incorporates thousands to millions of mutated variant epitopes within a combinatorial library, to target extreme variability and intratumoral heterogeneity of tumor antigens. A single intrasplenic vaccination with a VEL DNA vaccine encoding the amino-terminal region of mouse survivin, carrying eight mutated amino acid positions, induced significant tumor growth inhibition and suppression of lung metastasis in an aggressive and highly metastatic 4T1 triple-negative breast cancer (TNBC) preclinical model. Combining this vaccine with an immune checkpoint inhibitor (ICI) αCTLA-4 resulted in the elimination of established tumors, tumor-free survival of up to 412 days and life-long sterile immunity against tumor rechallenge in 77 % of mice. A significant increase in the number of CD3 CD8 Ly6C effector T cells in the lungs and spleens of vaccinated mice and the presence of central memory (T) and effector memory (T) T cells at different time points was documented. Likewise, the reduction of numbers of CD11b Ly6C Ly6G granulocytic myeloid-derived suppressor cells (G-MDSC) in vaccinated mice was observed. These data suggest that VEL immunogens are feasible candidates for inclusion/testing in clinical trials targeting multiple cancer types due to their universal nature.
Trogocytosis-mediated acquisition of MHC class II molecules from plasmacytoid dendritic cells confers donor-specific immune tolerance to CD8CD45RC regulatory T cells.
Zhao Y, Zhou L, Yuan ZH … +7 more , Jia YN, Chen Q, Ren ZY, Zhang XX, Lang R, He Q, Li XL
Mol Immunol · 2025 Aug · PMID 40482606 · Publisher ↗
OBJECTIVE: Donor-specific suppression by MHC-IICD8CD45RCregulatory T cells (Tregs) was observed in our prior study, here we endeavor to investigate the mechanism underlying generation of the MHC-IICD8CD45RCTregs. METHODS...
OBJECTIVE: Donor-specific suppression by MHC-IICD8CD45RCregulatory T cells (Tregs) was observed in our prior study, here we endeavor to investigate the mechanism underlying generation of the MHC-IICD8CD45RCTregs. METHODS: The presence of MHC-IICD8CD45RCTregs within tolerated grafts was confirmed using a multicolor immunofluorescence technique in spontaneous tolerant rat liver transplant model. We aimed to elucidate the generation mechanism of MHC-IICD8CD45RCTregs by purifying naive CD8CD45RCTregs and plasmacytoid dendritic cells (pDCs) from recipients and co-culturing them to induce trogocytosis. Initially, we examined the immunophenotype and cytokine secretion of MHC-IICD8CD45RCTreg using flow cytometry. Trogocytosis of peptide-MHC class II complexes was visualized using a confocal microscope. Subsequently, we analyzed the donor-specific inhibitory effect of MHC-IICD8CD45RCTregs using CFSE-based lymphocyte proliferation analysis. Finally, we explored the possible transfer mechanisms of MHC class II using IFN-γ stimulation and 1-MT to block indoleamine-(2,3)-dioxygenase (IDO). RESULTS: In the spontaneously tolerant rat liver transplants, MHC-IICD8CD45RCTregs and IL-10 expression were upregulated. Our in vitro study revealed that trogocytosis occurring between naive CD8CD45RCTregs and pDCs could induce MHC-IICD8CD45RCTregs. The semi-direct pathway represents the primary mode of Trogocytosis-mediated transfer of MHC-II molecules from pDCs to CD8CD45RCTregs. The MHC-IICD8CD45RCTregs exhibited high secretion of IL-10 and IFN-γ. Co-culturing with MHC-IICD8CD45RCTregs significantly suppressed the proliferation of CD4CD25effector T cells. Moreover, this inhibitory effect was donor-specific and could be overcome in the presence of third-party antigen-presenting cells. Our data also suggested that blocking the IFN-γ/IDO signaling pathway could inhibit the generation of trogocytosis-mediated MHC-IICD8CD45RCTregs. CONCLUSIONS: MHC-IICD8CD45RCTregs generated through trogocytosis exhibit donor-specific suppressive function. Moreover, in vitro generation of MHC-IICD8CD45RCTregs offers a potential alternative approach to induce donor-specific immune tolerance through adoptive transfer.
NSUN3-mediated mC modification of TAK1 promotes sepsis-induced pulmonary injury through regulating inflammation.
Wang J, Ding Z, Wu B
Mol Immunol · 2025 Aug · PMID 40482605 · Publisher ↗
BACKGROUND: Sepsis-induced pulmonary injury (SPI) is a life-threatening condition with high mortality. This study aimed to investigate the role of NOP2/Sun RNA methyltransferase 3 (NSUN3) in SPI and its underlying mechan...
BACKGROUND: Sepsis-induced pulmonary injury (SPI) is a life-threatening condition with high mortality. This study aimed to investigate the role of NOP2/Sun RNA methyltransferase 3 (NSUN3) in SPI and its underlying mechanisms. METHODS: Bioinformatics analysis of the GSE10474 dataset revealed differentially expressed genes in acute lung injury. A cecum ligation and puncture (CLP) rat model was established. Lung injury was evaluated via hematoxylin and eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect inflammatory cytokine mRNA expression and protein levels. In vitro, human lung microvascular endothelial cells (HULEC-5a) were treated with lipopolysaccharide and transfected with NSUN3-silencing or TAK1-overexpression vectors. Methylated RNA immunoprecipitation (MeRIP) and dual-luciferase assays were conducted to investigate the interactions between NSUN3 and transforming growth factor β-activated kinase 1 (TAK1). RESULTS: NSUN3 expression was upregulated in CLP-induced rat lung tissues and LPS-stimulated HULEC-5a cells. NSUN3 inhibition attenuated lung injury and decreased inflammatory cytokine levels in both models. Mechanistically, NSUN3-mediated m⁵C modification enhanced TAK1 mRNA stability in HULEC-5a cells. TAK1 overexpression counteracted the anti-inflammatory effects induced by NSUN3 knockdown. CONCLUSION: NSUN3-mediated mC modification of TAK1 promoted SPI through regulating inflammation, providing a new insight for SPI treatment.
Psoralidin induces pyroptosis in both tumor cells and macrophages as well as enhances nature killer cell cytotoxicity to suppress hepatocellular carcinoma.
Wang X, Xie Y, Yang H … +14 more , Li C, Wen X, Chen S, Yao Q, Zheng C, Li C, He C, Fang M, Shi C, Huang A, Zhang P, Bai Z, Zhan X, Xiao X
Mol Immunol · 2025 Aug · PMID 40479862 · Publisher ↗
Psoralidin is a major component of the traditional Chinese medicine Psoraleae Fructus, which is derived from the dried mature fruit of the leguminous plant Psoralea corylifolia L. and possesses many pharmacological effec...
Psoralidin is a major component of the traditional Chinese medicine Psoraleae Fructus, which is derived from the dried mature fruit of the leguminous plant Psoralea corylifolia L. and possesses many pharmacological effects, including anti-tumor effects. However, the mechanism through which psoralidin protects against hepatocellular carcinoma (HCC) remains unclear. In our study, we found that psoralidin induced pyroptosis and gasdermin E (GSDME) cleavage in HepG2 and Hepa1-6 cells, which were reversed by the caspase-3 inhibitor Z-DEVD-FMK. Moreover, psoralidin induced mitochondrial reactive oxygen species (ROS) production, leading to caspase-3 activation and subsequent GSDME cleavage. Interestingly, psoralidin induced pyroptosis in macrophages via ROS-NLRP3 inflammasome-gasdermin D (GSDMD), leading to the secretion of interleukin (IL)-1β and IL-18, which promoted natural killer (NK) cell activation and its anti-tumor capability. In a mouse model, psoralidin suppressed HCC growth, induced tumor cell pyroptosis, and enhanced tumor infiltration of T and NK cells. Collectively, our data demonstrate that psoralidin induces pyroptosis in tumor cells via ROS/caspase-3/GSDME and triggers pyroptosis in macrophages via ROS/NLRP3 inflammasome/GSDMD, enhancing NK cell anti-tumor ability, suggesting that psoralidin could be used as a potential therapeutic candidate for HCC.
CRISPR-Cas9 engineering of human T regulatory cells - Design and optimization of a manufacturing process.
Shimon O, Dean AM, Cohen S … +5 more , Moser AL, Dacso CC, Gilad Y, Lonard DM, O'Malley BW
Mol Immunol · 2025 Aug · PMID 40472724 · Publisher ↗
Regulatory T cells (Tregs) are a subset of CD4 + T cells that comprise 5-10 % of the total CD4 + T cell population. Tregs, which are critically important for the maintenance of immune tolerance and immune homeostasis, ar...
Regulatory T cells (Tregs) are a subset of CD4 + T cells that comprise 5-10 % of the total CD4 + T cell population. Tregs, which are critically important for the maintenance of immune tolerance and immune homeostasis, are distinguished from other subtypes of CD4 + T cells by the expression of the transcription factor FOXP3. Because of the centrality to immunoregulation, Tregs have gained increasing attention as promising targets for clinical applications in autoimmune diseases, transplant rejection and graft-versus-host disease (GvHD). However, the essential role of Tregs in the complex network of the immune system implies their targeting as a promising therapeutic approach also in other medical indications, such as neurodegenerative diseases and cancer. Our group recently published a study showing that genetically modified Tregs are capable of clearing solid malignancies in various mice models, including an aggressive triple negative breast cancer (TNBC) and prostate cancer, which provides the impetus to develop an adoptive cell therapy using Steroid Receptor Coactivator 3 (SRC-3) knock out (KO) Tregs. It is well known that isolation, genetic editing and the expansion of Tregs as a homogenous and healthy population present specific technical challenges. In this context, here we outline the development of a process for the production of SRC-3 KO human Tregs (hTregs), which can subsequently be adapted for Current Good Manufacturing Practice (cGMP) settings to facilitate clinical-scale production.
SAA1 deletion ameliorates cardiac injury after myocardial infarction by promoting macrophage transformation to reparative subtype.
Xu Y, Zhang K, Sun C … +8 more , Zhang Q, Li B, Yuan Y, Wang J, Zhang J, Chang Y, Wang S, Li J
Mol Immunol · 2025 Aug · PMID 40460795 · Publisher ↗
BACKGROUND: The regulation of M1/M2 macrophage phenotypic conversion is an effective therapeutic strategy for post-myocardial infarction (MI). Serum Amyloid A1 (SAA1) is an acute-phase protein that plays an important rol...
BACKGROUND: The regulation of M1/M2 macrophage phenotypic conversion is an effective therapeutic strategy for post-myocardial infarction (MI). Serum Amyloid A1 (SAA1) is an acute-phase protein that plays an important role in regulating inflammatory responses. However, its function in modulating macrophage polarization post-MI remains unclear. METHODS: To achieve macrophage-specific manipulation of SAA1 expression in vivo, adeno-associated virus 9 (AAV9) vectors driven by a macrophage-specific promoter (F4/80) were used to either knockdown (AAV9-F4/80-sh-SAA1) or overexpress (AAV9-F4/80-SAA1) SAA1. Two weeks after the virus injection, mice underwent MI and ischemia-reperfusion (I/R) surgery. Each group included six mice. Immunofluorescence (IF), western blotting, and quantitative real-time polymerase chain reaction were performed to explore the mechanisms underlying SAA1-induced macrophage polarization and cardiac injury after MI and I/R. SAA1 was overexpressed and knocked down in lipopolysaccharide-stimulated bone marrow-derived macrophages in vitro using plasmids and siRNA. IF, western blotting, and quantitative real-time polymerase chain reaction were used to measure macrophage polarization and inflammatory responses. RESULTS: We detected a significant increase in SAA1 levels in human and mouse peripheral blood mononuclear cells after MI and I/R. Following SAA1 knockout, left ventricular ejection fraction (64.33 ± 2.35 % versus 40.97 ± 8.36 %) was significantly improved and infarcted size (93.95 ± 3.79 % versus 29.76 ± 17.05 %) was markedly reduced in MI+AAV-9-F4/80-Sh-SAA1 compared with MI+AAV-9-F4/80-Sh-NC. Similarly, the accumulation of M1 macrophages in the infarcted tissues was reduced by SAA1 deletion. Mechanistically, these effects were partially mediated by inhibition of via the p38 MAPK signaling pathway. CONCLUSION: SAA1 activated the p38 MAPK pathway to contribute to macrophage polarization and the release of inflammatory factors and subsequently exacerbated cardiac injury and inflammatory response post-MI and I/R.
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