Cellular & Molecular Immunology[JOURNAL]
Sun
200 papers
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.
Andrographolide and its sulfated metabolite alleviated DSS-induced inflammatory bowel disease through regulating inflammation and immune via MAPK/NLRP3 pathways and the balance of Th17/Treg cells.
Zhang HL, Chang J, Sun CP … +10 more , Huo ZP, Feng YL, Li PY, Jia YX, Hui SW, Zhu QM, Cai JY, He Y, Qiu F, Zhang J
Mol Immunol · 2025 Jul · PMID 40441031 · Publisher ↗
Inflammatory Bowel Disease (IBD), is a chronic illness characterized by severe abdominal pain, diarrhea, and weight loss, seriously diminishing patients' quality of life. Andrographolide (AND), a natural diterpenoid from...
Inflammatory Bowel Disease (IBD), is a chronic illness characterized by severe abdominal pain, diarrhea, and weight loss, seriously diminishing patients' quality of life. Andrographolide (AND), a natural diterpenoid from Andrographis paniculata, and its sulfated metabolite, andrographolide sodium bisulfite (ASB), have showed potential anti-inflammatory effects. However, their mechanism in IBD remains elusive. This study investigated the impact of AND and its sulfated derivative ASB, on inflammatory responses in IBD. Our findings revealed that AND and ASB significantly reduced disease activity index (DAI) scores and enhanced intestinal barrier function in dextran sodium sulfate (DSS)-induced mice, thereby ameliorating the course of IBD. Furthermore, AND and ASB inhibited both the mitogen-activated protein kinase (MAPK) and NLRP3 pathways to reduce the release of inflammatory cytokines IL-6 and TNF-α. This mechanism was accompanied by a restoration of immune balance through the modulation of T-helper 17 (Th17) and regulatory T (Treg) cells. The ability of AND and ASB to mitigate chronic inflammation and maintain immune equilibrium presented a promising therapeutic approach for IBD management. These findings suggested that AND and ASB might provide novel therapeutic approaches for IBD, thereby warranting further investigation into their clinical efficacy for disease treatment and maintenance of remission.
Comparative transcriptomic analyses of macrophages infected with Toxoplasma gondii strains of different virulence provide molecular insights into the response of macrophage in phagocytosis and polarization to infection.
Zhu S, Liu J, Xu K … +12 more , Xu F, Jiang Y, Dai L, Pei T, Zhu Y, Liu D, Zhang X, Xu J, Yang J, Pan Z, Tao J, Hou Z
Mol Immunol · 2025 Jul · PMID 40414092 · Publisher ↗
Macrophages are essential for the proliferation and spread of Toxoplasma gondii. Modulating macrophage activation to improve the inflammatory environment is an effective approach for disease treatment. However, the molec...
Macrophages are essential for the proliferation and spread of Toxoplasma gondii. Modulating macrophage activation to improve the inflammatory environment is an effective approach for disease treatment. However, the molecular mechanism through which T. gondii alters macrophage function remain unknown. Based on transcriptomic data analysis of various macrophage types infected with T. gondii, current research revealed differences in the regulation of macrophage functions among strains with different virulence: RH was primarily involved in cell cycle regulation, ME49 was associated with cAMP signaling, and CEP mainly participated in ion channel activity. All three T. gondii strains were involved in regulating immune response activation, including leukocyte adhesion and the MAPK signaling pathway. Nineteen shared DEGs associated with macrophage phagocytosis or polarization were identified through the GeneCards database, and PPI analysis confirmed Il6 as the hub gene in the regulatory network. In vivo and in vitro experiments showed that the YZ-1 strain significantly regulated the expressions of eight DEGs (Il6, Rel, Cd83, Myc, Adora2b, Egr2, Gja1 and Nr4a2), and promoted macrophage phagocytic activity and induced M1 polarization, confirming a significant correlation with Il6. This study revealed the dissimilarities and commonalities in macrophage function regulated by T. gondii strains of different virulence, and identified key molecules involved in the regulation of macrophage phagocytosis and polarization during T. gondii infection. This is crucial for identifying potential drug targets against T. gondii and provides a new perspective on the etiopathogenesis and therapeutic approaches for toxoplasmosis.
Indications of trained innate immunity by Escherichia coli vaccination or chitin feed supplementation assessed during Ascaridia galli infection in chickens.
Moosavi M, Brødsgaard Kjærup R, Papanikolaou K … +2 more , Wattrang E, Sørensen Dalgaard T
Mol Immunol · 2025 Jul · PMID 40414091 · Publisher ↗
Infections with the gastrointestinal roundworm Ascaridia galli, cause health problems and economic losses in laying hen husbandry, particularly in organic and free-range systems. This study aimed to evaluate induction of...
Infections with the gastrointestinal roundworm Ascaridia galli, cause health problems and economic losses in laying hen husbandry, particularly in organic and free-range systems. This study aimed to evaluate induction of trained innate immunity through priming with a live attenuated Escherichia coli vaccine or chitin supplementation in the feed as a novel approach to mitigate A. galli infection. The study comprised four groups of chickens: chitin-fed (day 1-7 of age), E. coli-vaccinated (day 1 of age), an untreated control group, and a naïve uninfected group. On day 7 of age, the first three groups were infected with A. galli. Immune parameters were assessed after initial treatments and post the parasite infection. Also, faecal excretion of nematode eggs and total worm burden were monitored post-infection. The chitin and E. coli treatments induced changed proportions of leukocytes in bone marrow as well as changes in cell surface receptor expression. Moreover, treatments altered the immune response to the A. galli infection, e.g. observed for numbers of heterophils and TCRγδ+CD8- T-cells in the circulation but also expression levels of cell surface receptors CD41/61, Bu-1 and MHC-II on circulating leukocyte subsets. However, neither treatment affected worm burden, faecal egg excretion or the induction of A. galli-specific IgY. The results demonstrate potential in vivo training of the avian innate immune system but further research is needed to identify strategies to explore this in relation to control of nematode infections.
Helicobacter pylori delays neutrophil apoptosis but also drives the formation of cells with a leaky plasma membrane: Implications for inflammation.
Thai TD, Kamsom C, Phoksawat W … +5 more , Nithichanon A, Faksri K, Sripa B, Edwards SW, Salao K
Mol Immunol · 2025 Jul · PMID 40412278 · Publisher ↗
Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is a significant public health concern in countries in the Lower Mekong Basin. OV is a reservoir for Helicobacter pylori (H. pylori), and so many individuals a...
Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is a significant public health concern in countries in the Lower Mekong Basin. OV is a reservoir for Helicobacter pylori (H. pylori), and so many individuals are co-infected with these two biological carcinogens. Our study aimed to investigate interactions between H. pylori isogenic strains possessing or lacking the pathogenicity factor CagA (cagA+ and cagA-) with neutrophils. Both H. pylori strains were co-cultured with neutrophils in vitro, and neutrophil activation, phagocytosis, reactive oxygen species (ROS) production, and cell survival/apoptosis were measured. Both isogenic strains of H. pylori stimulated phagocytosis and while the cagA- strain induced slightly higher ROS production, both strains served as potent activators of neutrophils. Notably, H. pylori induced rapid cell death in a sub-population of neutrophils after 30 min of co-incubation while extending the lifespan of the neutrophils that survived this initial cell death. This initial incubation resulted in the appearance of propidium iodide (PI)+ neutrophils, i.e. cells with a compromised plasma membrane that could result in the release of inflammation-promoting neutrophil contents. While significantly more viable neutrophils were detected after 24 h (and 48 h) incubation with H. pylori, those cells that did not survive also showed characteristics of a compromised plasma membrane (i.e. PI+). We propose that the combinations of PI+ neutrophils with leaky plasma membranes and non-apoptotic neutrophils with enhanced survival after incubation with H. pylori may drive persistent inflammation. These findings offer new insights into the immunopathogenesis of OV and H. pylori co-infections, which may help improve OV treatment strategies.
LncRNA SNHG12 promotes EMT and metastasis of colorectal cancer via regulating TGF-β/Smad2/3 signaling pathway.
Zhao L, Chang Y, Sun X … +4 more , Chen H, Li N, Ma T, Jin S
Mol Immunol · 2025 Jul · PMID 40412277 · Publisher ↗
OBJECTIVE: In this study, we aimed to explore the molecular mechanism of SNHG12 promoting colorectal cancer (CRC) progression. METHODS: Bioinformatics technology was utilized to identify SNHG12-targeted mRNA and the corr...
OBJECTIVE: In this study, we aimed to explore the molecular mechanism of SNHG12 promoting colorectal cancer (CRC) progression. METHODS: Bioinformatics technology was utilized to identify SNHG12-targeted mRNA and the correlation with the prognosis of CRC patients. Transfected sequence of knockdown SNHG12 in HCT-116 cell line was established. CCK8 assay, colone formation assay, flow cytometry, cell migration and transwell assay were applied to detect the impact of SNHG12 on HCT-116 cells. Besides, qRT-PCR and western blot were employed to evaluate the apoptotic and EMT markers as well as the expression of TGF-β and p-Smad2/3. Additionally, the rescue test of overexpressing TGF-β and a nude mouse subcutaneous tumor model were established to validate the pivotal role of SNHG12 in driving the progression of CRC. RESULTS: SNHG12 could predict the prognosis of CRC patients, and a target mRNA GOLT1B was obtained from bioinformatics. In vitro results indicated that SNHG12 facilitated the proliferation, migration, and invasion of HCT-116 cells. qRT-PCR and western blot showed SNHG12 was related to the expression of Caspase 3, EMT markers as well as TGF-β and p-Smad2/3. Meanwhile, the rescue experiment proved that overexpressed TGF-β had the ability to reverse the impact of SNHG12 knockout on cell function and phenotype. In vivo, SNHG12 knockdown significantly reduced tumor growth. CONCLUSION: SNHG12 promotes EMT and metastasis of CRC by modulating the TGF-β/Smad2/3 signaling pathway and EMT process, which could function as a prognostic biomarker and a treatment target for CRC.
NLRP3 regulates macrophage function by M-CSF/M-CSFR signaling in acute radiation-induced lung injury.
Feng Y, Kong J, Sun W … +7 more , Li Y, Ren F, Sun X, Li M, Liu Y, Sun S, Qin H
Mol Immunol · 2025 Jul · PMID 40403643 · Publisher ↗
Alveolar macrophages are the most abundant macrophages in the healthy lungs and are important players in maintaining lung homeostasis as well as orchestrating tissue repair after injury. Many studies have proved that the...
Alveolar macrophages are the most abundant macrophages in the healthy lungs and are important players in maintaining lung homeostasis as well as orchestrating tissue repair after injury. Many studies have proved that the initiation, development and progression of acute radiation-induced lung injury are associated with alveolar macrophages. However, lung-associated macrophages function and developmental processes in acute radiation-reduced lung injury remain elusive. To investigate the role of NLRP3 in radiation-reduced lung injury, we established wild-type and NLRP3 mice models, and we found that the extent of pneumonia reduced in NLRP3 IR group. In in vivo experiments, we observed a decrease in the number of macrophages in NLRP3 group. At the same time, in in vitro experiments we have found that macrophages are more easily polarized toward the M2 after radiation in NLRP3 group compared with the control group. Our findings reveal that NLRP3 affects the differentiation and chemotaxis of alveolar macrophages through M-CSF/M-CSFR signalling at the onset of radiation-induced lung injury.
TSPAN15 enhances EMT-mediated metastasis of HCC by promoting autophagy through BTRC-mediated PDCD4 degradation.
Shao Z, Hao Q, Chen J … +1 more , Lu Y
Mol Immunol · 2025 Jul · PMID 40398082 · Publisher ↗
BACKGROUND: Cumulative evidence shows that Tetraspanin 15 (TSPAN15) shows a high degree of consistency in a variety of tumor characteristics, which has attracted extensive attention from researchers. We used TSPAN15 as a...
BACKGROUND: Cumulative evidence shows that Tetraspanin 15 (TSPAN15) shows a high degree of consistency in a variety of tumor characteristics, which has attracted extensive attention from researchers. We used TSPAN15 as a starting point to explore the role and mechanism of TSPAN15 in in hepatocellular carcinoma (HCC). METHODS: Using database analysis, recombinant plasmid transfection technology, transwell, autophagic flux analysis and western blotting, the effects of TSPAN15 on autophagy, invasion, epithelial-mesenchymal transition (EMT) of HCC cells, and tumor growth and metastasis were elucidated after silencing TSPAN15 in HCC cells. The effect of TSPAN15 on tumor growth was detected by using xenograft model of nude mice. RESULTS: Based on the online database and immunohistochemistry analysis, it was found that the mRNA and protein expression of TSPAN15 in HCC tissues was significantly higher than that in normal liver tissues or adjacent non-cancerous tissues. High expression of TSPAN15 was an independent risk factor for poor prognosis in TCGA-LIHC patients. TSPAN15 silencing inhibited HCC autophagy and autophagy-induced migration, invasion and EMT as well as tumor growth and metastasis. Mechanistically, TSPAN15 contributed to programmed cell death 4 (PDCD4) proteasomal degradation through physical interaction with beta-transducin repeat containing (BTRC), thus activing autophagy. Rescue experiments revealed that PDCD4 effectively inhibited TSPAN15-induced autophagy, migration, invasion and EMT. CONCLUSION: Abnormally expressed TSPAN15 promotes the degradation of tumor suppressor gene PDCD4 through ubiquitination, thereby promoting autophagy and autophagy-mediated EMT and metastasis of HCC cells, demonstrating the importance of TSPAN15 in the molecular etiology of HCC and its potential therapeutic value.
Total free lipids from MDR strain of Mycobacterium tuberculosis "M" reduce T cell activation and CTL activity in healthy individuals.
Mercedes Bigi M, Imperiale B, Soria M … +3 more , López B, Bigi F, de la Barrera S
Mol Immunol · 2025 Jul · PMID 40382835 · Publisher ↗
Increasing evidence highlights the role of cell wall components in the effectiveness of different Mycobacterium tuberculosis (Mtb) strains in modulating host immune response. We previously demonstrated that the outbreak...
Increasing evidence highlights the role of cell wall components in the effectiveness of different Mycobacterium tuberculosis (Mtb) strains in modulating host immune response. We previously demonstrated that the outbreak multidrug-resistant strain M displays a distinctive lipid profile in its cell envelope compared to the closely related sporadic strain 410. Both strains markedly differ in their ability to induce fully functional CD8 T cells because of low CD69 signaling and impaired CD4 T cell help. In this study, we evaluated the impact of extractable lipids (LP) from M (LP-M) and 410 (LP-410) on the activation and functionality of T cells from healthy individuals. PBMCs were cultured alone or with Mtb in the presence or absence of LP-M, LP-410, or LP from CD1551 mutants in polymorphic genes between M and 410. Then, surface CD69 and intracytoplasmic IL-2 (after 3 days of culture), as well as surface CD107 expression (after 6 days of culture) were determined in T cells by flow cytometry. In contrast to LP-410, LP-M induced low expression of CD69 and IL-2 in CD4/CD8 cells and of CD107 in CD8 cells. Besides, LP from Mtb strains mutated in Rv1861c and Rv3787c genes inhibited H37Rv-induced T cell response without causing cell death. Thus, our results suggest that LP-M likely through mutations in Rv1861 and Rv3787c, inhibits the activation and functionality of T cells from PPD+ healthy human donors and might partially contribute to the development of immune evasion mechanisms in the M strain.
The mA demethylase FTO controls Th1 differentiation and immunity against infections.
Yao Z, Sun L, Gao Y … +8 more , Su Y, He B, Ge Y, Yang C, Jia X, Jiao A, Sun C, Zhang B
Mol Immunol · 2025 Jul · PMID 40378511 · Publisher ↗
Antigen-specific effector CD4 T cells are critical for defense against exogenous pathogens. However, the epigenetic mechanisms underlying CD4 T cell immune responses, particularly RNA modifications, remain incompletely u...
Antigen-specific effector CD4 T cells are critical for defense against exogenous pathogens. However, the epigenetic mechanisms underlying CD4 T cell immune responses, particularly RNA modifications, remain incompletely understood. In this study, we employed a T cell-specific deletion of the fat mass and obesity-associated protein (FTO), a key N6-methyladenosine (mA) demethylase, to elucidate its role in CD4 T cell mediated immunity. Our findings demonstrate that FTO is essential for maintaining CD4 T cell immune responses and protective functions. Specifically, FTO deficiency restricts the expansion of CD4 T helper (Th)1 effector cells following antigen challenge and results in decreased expression of T-bet and IFN-γ in Th1 cells. Additionally, FTO deficient CD4 T cells exhibit impaired pathogen elimination. Collectively, our study reveals a novel epigenetic regulatory mechanism in supporting CD4 T cell differentiation, providing new insights into the post-transcriptional regulation of CD4 T cell immunity and highlighting the potential for therapeutic strategies.
Cordycepin ameliorates high glucose-induced proliferation, inflammation, and extracellular matrix deposition in glomerular mesangial cells through Smad7-dependent manner.
Han W, Chen S, Ma B … +7 more , Deng Z, Li J, Tang C, Lu Z, Li S, Zhang Q, Ma B
Mol Immunol · 2025 Jul · PMID 40373638 · Publisher ↗
Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease. The extracellular matrix deposition is potent pathogenic factors of renal fibrosis and injury. Cordycepin (Cor), a natural nucleoside...
Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease. The extracellular matrix deposition is potent pathogenic factors of renal fibrosis and injury. Cordycepin (Cor), a natural nucleoside compound from Cordyceps militaris, has been demonstrated reno-protective properties. Nevertheless, the role and underlying mechanism of Cor in DN have not been studied extensively. This study aimed to investigate the renal protective effects and mechanism of Cor on diabetic mouse models and high glucose (HG) induced-mouse glomerular mesangial cells (GMCs). The results of the biochemical indicators indicated that Cor could ameliorate renal dysfunction, as evidenced by reductions in serum creatinine, blood urea nitrogen, and urinary protein. Histological evaluation further confirmed that Cor ameliorated renal pathological changes, including mesangial matrix expansion, glomerular basement membrane thickening, glomerulosclerosis, and fibrillar collagen deposition. Additionally, Cor alleviated cell proliferation and fibrosis induced by high glucose in GMCs. Mechanistically, Cor upregulated the expression of Smad7, suppressed TGF-β/Smad pathway activation and its downstream NOX4-mediated NLRP3 inflammasome. Furthermore, knockdown of Smad7 by shRNA transfection abrogated the inhibiting effects of Cor in high glucose-induced GMCs. These findings suggested that Cor represented a promising therapeutic candidate for mitigating renal damage in diabetic nephropathy. The underlying mechanism involved the enhancement of Smad7 expression, which in turn suppresses TGF-β/Smad signaling and NOX4-mediated NLRP3 inflammasome activation.
Targeted p38 mitogen-activated protein kinase inhibition potently augment inflammatory responses of human macrophages toward Staphylococcus aureus.
Lund A, Moffat D, Jepsen SD … +5 more , Desler C, Andresen L, Bregenholt S, Reddy V, Skov S
Mol Immunol · 2025 Jul · PMID 40373637 · Publisher ↗
Antibiotic-resistant Staphylococcus aureus (S. aureus) is a growing challenge for human health and novel treatment options are needed. Here we examine a novel therapeutic approach against persistent S. aureus infections...
Antibiotic-resistant Staphylococcus aureus (S. aureus) is a growing challenge for human health and novel treatment options are needed. Here we examine a novel therapeutic approach against persistent S. aureus infections based on monocyte/macrophage specific inhibition of the p38α mitogen-activated protein kinase activity. Since systemic p38α kinase inhibition cause aberrant toxicity, we used the myeloid specific p38α kinase inhibitor, MPL-5821. P38α kinase inhibition caused a potent increase in the pro-inflammatory profile of human macrophages after exposure to S. aureus, including upregulation of M1-markers and induction of pro-inflammatory cytokines including IFN-γ, TNF-α, IL-1β, IL12p70, IL-6 and IL-8, as well as an increase in phagocytic capacities. These pro-inflammatory signals were only seen after combined S. aureus exposure and p38α inhibition. Macrophages are often regulated by changes in intracellular metabolism. In agreement with this, the combination of S. aureus exposure and p38α inhibition led to specific changes in glycolytic and mitochondrial activity within the responding macrophages. Our study thus unravels a novel and specific activation of macrophages that augment their response toward S. aureus, without causing aberrant inflammation. This constitutes a unique non-antibiotic therapeutic approach that can potentially be used against persistent S. aureus infection.
Phillyrin for sepsis-related acute lung injury: A potential strategy suppressing GSK-3β.
Yang G, Tan W, Yan L … +11 more , Lao Q, Zheng W, Ding H, Yu J, Liu Y, Zou L, Guo M, Yu L, Zhou X, Li W, Yang L
Mol Immunol · 2025 Jul · PMID 40359720 · Publisher ↗
The efficacy of clinical drugs for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains suboptimal. Phillyrin (PHN), a compound derived from Forsythia, is believed to alleviate sepsis-related ALI/ARDS...
The efficacy of clinical drugs for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains suboptimal. Phillyrin (PHN), a compound derived from Forsythia, is believed to alleviate sepsis-related ALI/ARDS; however, its mechanisms are not fully elucidated. In this study, we screened 8331 target genes associated with ALI/ARDS from public databases and identified six hub genes relevant to PHN treatment: AKT1, GSK-3β, PPP2CA, PPP2CB, PPP2R1A, and AR. Receiver operating characteristic analysis and single-cell sequencing analysis revealed the expression of AKT1, GSK-3β, PPP2CA, PPP2CB, and PPP2R1A were markedly elevated. Molecular docking and dynamics simulations indicated that PHN forms a structurally stable complex with glycogen synthase kinase-3β (GSK-3β). Mendelian randomization analyses suggested that PHN, as a potent GSK-3β inhibitor, may promote M2 macrophage polarization and reduce neutrophil recruitment. We validated these findings through in vivo and in vitro experiments, demonstrating that PHN lowers iNOS levels and raises MMR levels by downregulating GSK-3β mRNA expression and protein activity during lipopolysaccharide (LPS)-induced macrophage inflammation. Additionally, PHN inhibited GSK-3β mRNA expression and protein activity, reducing NF-κB-p65 nuclear translocation in LPS-induced zebrafish inflammation and mice ALI. This inhibition decreased levels of TNF-α and IL-6, increased IL-10 levels, promoted M2 macrophage polarization, suppressed neutrophil recruitment, and ultimately ameliorated ALI/ARDS. In conclusion, our results indicate that PHN effectively alleviates LPS-induced ALI/ARDS by suppressing GSK-3β signaling.
Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells.
Huang F, Cao X, Mei J … +5 more , Wu C, Zhu W, Sun L, Dai C, Wang M
Mol Immunol · 2025 Jul · PMID 40347782 · Publisher ↗
Metabolic reprogramming, exemplified by the "Warburg effect," is a hallmark of human cancers, leading to lactate buildup in tumors. Bone marrow-derived mesenchymal stem cells (BM-MSCs), key contributors to cancer-associa...
Metabolic reprogramming, exemplified by the "Warburg effect," is a hallmark of human cancers, leading to lactate buildup in tumors. Bone marrow-derived mesenchymal stem cells (BM-MSCs), key contributors to cancer-associated fibroblasts (CAFs), integrate into gastric cancer stroma through interactions with cancer cells. However, the role of lactate in activating BM-MSCs in this context remains unclear. Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965. Gastric cancer cells released more lactate under hypoxia than normoxia. While normoxic gastric cancer cells could educate BM-MSCs, hypoxic cells were more effective. However, the effects of the supernatant from gastric cancer cells in both conditions were significantly reduced by AZD3965. Similarly, prevention of lactate production by oxamic acid sodium significantly reduced the effects observed. Lactate-activated BM-MSCs showed NF-κB signaling activation, increased IL-8 secretion, and no change in TGF-β signaling. These activated BM-MSCs promoted gastric cancer cell migration and invasion through IL-8 secretion and enhanced resistance to CD8 + T cell cytotoxicity by upregulating PD-L1. Collectively, gastric cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric cancer.
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