Cellular & Molecular Immunology[JOURNAL]
Sun
200 papers
Gelatin enhances bacteria-phagocytosis via a ROS-mitochondria-STING axis in differentiated human macrophage-like U937 cells.
Sun X, Li M, Ma Y … +9 more , Chen K, Jiang S, Hayashi T, Itoh K, Mizuno K, Hattori S, Fujisaki H, Liu W, Ikejima T
Mol Immunol · 2025 Oct · PMID 40815890 · Publisher ↗
The recruitment of macrophages to a pathological site is accompanied by the change in surrounding extracellular matrix. The pathological foci in a highly inflammatory status contain certain amounts of gelatin, the denatu...
The recruitment of macrophages to a pathological site is accompanied by the change in surrounding extracellular matrix. The pathological foci in a highly inflammatory status contain certain amounts of gelatin, the denatured form of collagen. We previously revealed that precoating the cell dishes with gelatin, but not type I collagen, enhances bacteria-phagocytosis capacity of phorbol 12-myristate 13-acetate (PMA)-treated macrophage-like human histiocytic lymphoma U937 cells. The present study further reveals that gelatin-precoating increases the amount of reactive oxygen species (ROS) in PMA-treated U937 cells, which contributes to the enhanced phagocytosis of bacteria, including both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. ROS in cells on gelatin-precoated culture plates cause impairments on mitochondria, as shown by the reduced mitochondrial membrane potential and ATP levels, as well as the increase in oxidative lesions in mitochondrial DNA. These mitochondrial damages lead to the activation of stimulator of interferon genes (STING) pathway, which enhances the bacteria-phagocytosis in PMA-treated U937 cells. Simultaneously, mitophagy-related proteins, such as PINK1, parkin and LC3 II, all increase following the elevation of ROS levels. Of note, mitophagy restricts the mitochondrial disorders, forming a feedback negative regulation for the effects of ROS, and works against bacteria-phagocytosis. This study reveals a core function of ROS-mitochondria-STING axis during gelatin-enhanced bacteria-phagocytosis in PMA-stimulated macrophage-like U937 cells, and provides possibility for clinically applying gelatin as a protectant for bacterial infection in some lesions.
YY1/INSIG1 enhances atherosclerosis progression by regulating AMPK-mTOR signaling.
Yang M, Zhang J, Xu Z … +2 more , Yang L, Tang S
Mol Immunol · 2025 Oct · PMID 40815888 · Publisher ↗
OBJECTIVE: The regulatory mechanisms of Insulin-Induced Gene 1 (INSIG1) in atherosclerosis (AS) remain largely unknown. This study aimed to investigate the role of the YY1/INSIG1 axis and its regulation of the AMPK-mTOR...
OBJECTIVE: The regulatory mechanisms of Insulin-Induced Gene 1 (INSIG1) in atherosclerosis (AS) remain largely unknown. This study aimed to investigate the role of the YY1/INSIG1 axis and its regulation of the AMPK-mTOR signaling pathway in AS pathogenesis. METHODS: Atherosclerosis mouse models were established. RNA sequencing was performed to determine differentially expressed genes. Human umbilical vein endothelial cells (HUVECs) and human vascular smooth muscle cells (HVSMCs) were treated with ox-LDL and/or transfected with plasmids for INSIG1. Cellular functions were evaluated by proliferation, migration, and inflammation assays. Key proteins in the AMPK/mTOR pathway were measured by western blotting. The regulation of INSIG1 by transcription factor YY1 was confirmed using a dual-luciferase reporter assay. Crucially, the functional role of the INSIG1-AMPK axis was validated in vivo using an AMPK inhibitor (Dorsomorphin, DM) in the AS mouse model. RESULTS: INSIG1 expression was significantly downregulated in atherosclerosis mouse models and patients. In HUVECs, INSIG1 promoted cell proliferation, migration, and invasion, while in HVSMCs, INSIG1 suppressed these functions. Higher INSIG1 levels reduced the proinflammatory mediators IL-6 and MCP-1. INSIG1 overexpression activated AMPK and inhibited mTOR phosphorylation. Crucially, in the mouse model, the protective anti-atherosclerotic effects of INSIG1 overexpression were significantly abolished by the administration of the AMPK inhibitor DM. Bioinformatics suggested a potential interaction between YY1 and INSIG1 in atherosclerosis, which was confirmed by a dual-luciferase reporter assay that demonstrated YY1 directly regulate the mRNA transcription of INSIG1. CONCLUSION: These findings underscore the relevance of INSIG1 and YY1 in atherosclerosis and maybe in its treatment.
PCBP2 alleviates myocardial infarction by inhibiting cardiomyocyte ferroptosis via the NDUFS1/NRF2 pathway.
Zhang Q, Jin A, Cheng H … +2 more , Zheng Y, Li B
Mol Immunol · 2025 Oct · PMID 40784311 · Publisher ↗
BACKGROUND: Poly(C) binding protein 2 (PCBP2) was reported to alleviate cardiomyocyte damage, but its molecular mechanism remains unclear. The current study aimed to investigate the role and potential mechanism of PCBP2...
BACKGROUND: Poly(C) binding protein 2 (PCBP2) was reported to alleviate cardiomyocyte damage, but its molecular mechanism remains unclear. The current study aimed to investigate the role and potential mechanism of PCBP2 in progression of MI. METHODS: An in vivo MI model was established by ligation of the left anterior descending (LAD) branch in mice. PCBP2 expression was detected in Normal and MI groups. H9C2 cells were treated with OGD for 0, 2, 4, and 6 h to screen for optimal time to establish MI model in vitro. H9C2 cells were transfected with pcDNA-PCBP2, and the effect of PCBP2 overexpression on OGD-induced oxidative stress, inflammation and ferroptosis was evaluated. Subsequently, the interaction of PCBP2 with NDUFS1 mRNA was predicted by the Starbase database and verified by RNA-immunoprecipitation (RIP) and RNA-protein pull-down assay. Next, a series of reversal experiments were performed to verify the regulation of PCBP2 on NDUFS1 expression. Then, pcDNA-NDUFS1 was transfected into H9C2 and MIND4-17 (NRF2 protein activator) treated for reversal experiments to assess the effect of NDUFS1 on NRF2-mediated ferroptosis. Finally, LV-PCBP2 and LV-NDUFS1 lentiviral vectors were intrapericardially injected into MI mice, and the role of PCBP2 and NDUFS1 in the progression of MI was verified in vivo. RESULTS: PCBP2 was downregulated in MI model and OGD-induced H9C2 cells. PCBP2 improved cell proliferation and inhibited oxidative stress, inflammation and ferroptosis in OGD-incubated H9C2 cells. PCBP2 bound with NDUFS1 mRNA and promoted NDUFS1 expression in H9C2 cells, which promoted NRF2 activation by enhancing NRF2 nuclear translocation and inhibited NRF2-mediated ferroptosis. Finally, administration of LV-PCBP2 and LV-NDUFS1 alleviated myocardial tissue injury and MI infarct in mice through suppressing cardiomyocyte ferroptosis and inflammation. CONCLUSION: Our results suggested that PCBP2 alleviated MI by inhibiting cardiomyocyte ferroptosis through interacting with NDUFS1 mRNA and activating NRF2-Keap1 pathway.
Luteolin attenuates type 2 inflammation in asthmatic mice induced by OVA by regulating IL-33/ST2- GSK3β-M2 macrophage polarization.
Huang X, Yu H, Zhou Y … +9 more , Xie C, Shi H, Chen M, Tang W, Chen W, Song J, Gao Z, Dong J, Luo Q
Mol Immunol · 2025 Oct · PMID 40752323 · Publisher ↗
Allergic asthma is a prevalent non-infectious inflammatory disease characterized by type 2 inflammation. Although multiple treatment options are available, their efficacy is often limited due to the heterogeneous nature...
Allergic asthma is a prevalent non-infectious inflammatory disease characterized by type 2 inflammation. Although multiple treatment options are available, their efficacy is often limited due to the heterogeneous nature of asthma. Luteolin (LUT), a naturally occurring flavonoid, has demonstrated therapeutic potential in various inflammatory conditions. The aim of this research is to investigate the underlying pathogenesis mechanisms of allergic asthma and to evaluate the therapeutic effects of LUT on allergic asthma via IL-33/ST2 signaling pathway. We established a murine model of allergic asthma by sensitizing and challenging BALB/c mice with ovalbumin (OVA), followed by treatment with LUT. The effects of LUT in allergic asthma mice were evaluated via the following techniques: pathological staining, Immunohistochemical staining (IHC), enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). Additionally, we also used IL-33 to stimulate RAW264.7 cells. Assays in vitro including cell counting Kit-8 (CCK-8), RT-qPCR and WB were performed to investigate potential mechanisms of LUT on IL-33/ST2 pathway activation and M2 macrophages polarization. LUT was verified to have crucial effects on ameliorating asthmatic mice lung function as evidenced by down-regulated airway resistance by 23 % and 48 % (p < 0.05 vs. OVA/saline group); regulating airway type 2 inflammation via decrease the content of type 2 inflammatory cytokines (IL-4, IL-5, and IL-13) by 17 %-78 % (**p < 0.01; p < 0.001 vs. OVA/saline group); decreasing airway inflammatory cells infiltration by 54 % and 65 % (p < 0.001 vs. OVA/saline group); inhibiting mucus secretion by 75 % and 89 % (p < 0.001 vs. OVA/saline group). Mechanistic research revealed that LUT can treat asthma via IL-33/ST2-GSK3β-M2 macrophages polarization pathway, thereby regulating airway inflammation, remodeling, and immune responses in allergic asthma. Collectively, these findings support LUT as a promising therapeutic agent for allergic asthma through targeted modulation of the IL-33/ST2-GSK3β-M2 macrophage polarization axis.
The role of microglia in neurodegenerative diseases.
Nie DA, Yu J, Huang W … +3 more , Li GH, He XY, Xu JH
Mol Immunol · 2025 Sep · PMID 40749622 · Publisher ↗
As resident immune surveillance cells within the central nervous system (CNS), microglia exert pivotal biological functions in maintaining CNS homeostasis through dynamic modulation of their proliferative capacity, chemo...
As resident immune surveillance cells within the central nervous system (CNS), microglia exert pivotal biological functions in maintaining CNS homeostasis through dynamic modulation of their proliferative capacity, chemotactic motility, efferocytosis activity, and biphasic secretory mechanisms involving both neuromodulatory factors and pro-inflammatory mediators. These specialized macrophages not only serve as the first line of defense in innate immunity but also orchestrate the regulation of adaptive immune responses; whose functional status directly governs both the physiological integrity of neural circuits and the progression of pathological outcomes. Notably, in neurodegenerative disease models, microglial functional states exhibit pronounced heterogeneity and are tightly regulated by microenvironmental cues. Upon encountering sustained hyperactivation or functional impairment, these cells precipitate a cascade of deleterious events within the neurovascular unit. Building upon these pathophysiological mechanisms, targeted modulation of microglial polarization equilibrium has emerged as a pivotal research focus in developing innovative neuroprotective therapeutic strategies. This review systematically integrates empirical evidence derived from cutting-edge methodologies-including molecular imaging, single-cell multi-omics profiling, and conditional genetic ablation-to mechanistically dissect the dual regulatory roles of microglia in orchestrating neural homeostatic maintenance and driving pathological progression in neurological disorders.
Choline reduces inflammatory response and lipid accumulation in calf hepatocytes induced by NEFA via inhibiting ROS/ NF-κB/NLRP3 inflammasome axis.
Zhang R, Du X, Hu H … +7 more , Chen J, Yu J, Wang L, Yao J, Liu S, Wang J, Cao Y
Mol Immunol · 2025 Sep · PMID 40743943 · Publisher ↗
Perinatal dairy cows are highly susceptible to fatty liver syndrome, a prevalent metabolic disorder characterized by excessive hepatic lipid accumulation. Although inflammatory progression drives the transition from phys...
Perinatal dairy cows are highly susceptible to fatty liver syndrome, a prevalent metabolic disorder characterized by excessive hepatic lipid accumulation. Although inflammatory progression drives the transition from physiological lipid storage to pathological steatosis, the underlying mechanisms remain incompletely understood. This study investigates the therapeutic potential of choline in non-esterified fatty acid (NEFA)-induced hepatic inflammation and lipid metabolism dysregulation using an in vitro calf hepatocytes model. A hepatic steatosis model was established by treating primary calf hepatocytes with 1.2 mM NEFA for 24 h. Choline supplementation (75 μM) significantly enhanced hepatocyte viability and reduced intracellular triglyceride (TG) content (P < 0.05). Transcriptomic analysis demonstrated that choline downregulated key components of the NLRP3 inflammasome (P < 0.05) and interleukin-1β (IL-1β) expression (P < 0.05). Mechanistically, choline attenuated NF-κB phosphorylation (P < 0.05) and suppressed intracellular reactive oxygen species (ROS) generation (P < 0.05), thereby inhibiting NLRP3 inflammasome assembly and subsequent IL-1β maturation (P < 0.05). Notably, activation of NLRP3 inflammasome complete abolished choline's protective effects on lipid homeostasis and inflammatory responses (P < 0.05). These findings demonstrate that choline ameliorates NEFA-induced hepatic steatosis by modulating the ROS/NF-κB-NLRP3-IL-1β/IL-18 signalling axis, providing novel therapeutic targets for intervention of steatohepatitis in periparturient dairy cows.
miR-146a-5p targets IRAK1/TRAF6 to promote bacillus Calmette-Guérin survival by exosome-mediated autocrine actions.
Chen HR, Huang HS, Zeng SY … +8 more , Sun YF, Chen L, Lai SY, Wang JJ, Yang F, Pi J, Cong YG, Xu JF
Mol Immunol · 2025 Sep · PMID 40730095 · Publisher ↗
BACKGROUND: Exosomes carry signaling molecules between cells and play important roles in the interaction between macrophages and Mycobacterium tuberculosis (Mtb). This study aimed to examine the function and content of e...
BACKGROUND: Exosomes carry signaling molecules between cells and play important roles in the interaction between macrophages and Mycobacterium tuberculosis (Mtb). This study aimed to examine the function and content of exosomes secreted by macrophages infected with Bacillus Calmette-Guérin (BCG). METHODS: THP-1 monocytes and HEK293T cells were used. Macrophages were infected with BCG. A Transwell system was used to evaluate the effect of the exosomes secreted by macrophages. Cells were transfected with the miR-146a-5p plasmid or inhibitor to examine the effects of miR-146a-5p overexpression or inhibition. qRT-PCR was employed to investigate the expression levels of miR-320a-5p, miR-27a-5p, miR-26a-5p, miR-146a-5p, and miR-223-5p and the mRNA expression of IL-6, TNF-α, and IL-1β. Western blot was used to investigate the protein expression of IRAK1, TRAF6, CD63, CD81, GRP94, Alix, TSG101, P65, and p-P65. A dual luciferase assay was performed to investigate whether miR-146a-5p targets IRAK1 and TRAF6. RESULTS: The infected cells contained high miR-146a-5p levels that could be secreted into exosomes. Exosomal miR-146a-5p promoted Mtb survival and proliferation after uptake by host cells. Bioinformatics showed that high miR-146a-5p levels were found in exosomes from BCG-infected macrophages and blood samples from patients with tuberculosis. The phagocytosis of exosomes containing miR-146a-5p by BCG-infected macrophages suppressed the expression of inflammatory factors by regulating the IRAK1-TRAF6-NF-κB signaling pathway, ultimately leading to the inhibition of inflammatory factor expression in macrophages and a decrease in the macrophage BCG killing capacity. CONCLUSION: The findings indicate a new immune evasion mechanism of Mtb. miR-146a-5p secreted in exosomes by BCG-infected macrophages can decrease the bactericidal potential of macrophages. The results offer a novel theoretical basis and potential biomarkers for diagnosing, treating, and managing tuberculosis.
Regulation of macrophage pyroptosis by SIRT1 during Pseudomonas aeruginosa-induced pneumonia.
Ding H, Xiao X, Zhan Y … +3 more , Lin Y, Xu C, Zeng Y
Mol Immunol · 2025 Sep · PMID 40714269 · Publisher ↗
Pseudomonas aeruginosa (PA), an opportunistic gram-negative bacterial pathogen, is the main cause of lung infections. Pulmonary infection induced by PA results in inflammatory lung injury characterized by macrophage pyro...
Pseudomonas aeruginosa (PA), an opportunistic gram-negative bacterial pathogen, is the main cause of lung infections. Pulmonary infection induced by PA results in inflammatory lung injury characterized by macrophage pyroptosis. In our study, a mouse model of pulmonary infection was established by tracheal intubation with PA in vivo, and the MH-S macrophage line was stimulated with PA in vitro. HE staining was performed to observe changes in the lung tissue. The mechanism was further explored through various methods, including flow cytometry, LDH release assays, ELISA, real-time PCR, Western blotting (WB), and CCK8 assays. Additionally, the effect of MH-S cells on the proliferation of alveolar endothelial cells was observed by coculturing these two cell types. The results showed that PA-induced inflammatory injury in murine lung tissues increased the levels of inflammatory factors (IL-1β/6/12) and pyroptosis-related proteins (NLRP3, Caspase 1/11, and GSDMD-N) and promoted pulmonary macrophage pyroptosis. PA downregulated Sirt1 expression and increased p-NF-κB-p65 levels both in vitro and in vivo. Sirt1 activation or overexpression alleviated PA-induced lung tissue injury, inhibited macrophage pyroptosis, and decreased the expression of inflammatory factors and pyroptosis-related proteins. Sirt1 inhibition or knockdown critically strengthened the effect of PA on pulmonary macrophage pyroptosis. NF-κB inhibition suppressed the PA-induced increase in Sirt1-regulated pyroptosis in MH-S macrophages, decreased the levels of inflammatory factors and pyroptosis-related proteins, and weakened the inhibitory effect of MLE-12 cell proliferation on PA-infected MH-S cells. In conclusion, the Sirt1/NF-κB axis negatively regulates PA-induced inflammatory factor release and macrophage pyroptosis, promotes lung epithelial cell proliferation, and reduces inflammatory injury to the lung tissue.
Leven PRO-CR mediates 5-HT and gut microbiota via TPH1 to improve slow-transit constipation.
Xia F, He Q, Wang S … +3 more , He M, Fang P, Yu Y
Mol Immunol · 2025 Sep · PMID 40712318 · Publisher ↗
Slow-transit constipation (STC) is a chronic disorder causing prolonged colonic transit and discomfort; this study explores the therapeutic potential of probiotics mixture (Leven PRO-CR) in modulating gut microbiota and...
Slow-transit constipation (STC) is a chronic disorder causing prolonged colonic transit and discomfort; this study explores the therapeutic potential of probiotics mixture (Leven PRO-CR) in modulating gut microbiota and enhancing intestinal motility. A loperamide-induced STC mouse model was established, and the effects of Leven PRO-CR treatment were evaluated by measuring defecation frequency, stool water content, and intestinal transit rate. Histopathological analyses, including Hematoxylin & Eosin (H&E) staining, immunohistochemistry (IHC), and TUNEL assay, were performed to assess colonic tissue integrity, interstitial cells of Cajal (ICCs) density, and apoptosis. The expression levels of serotonin (5-HT)-related markers (TPH1, 5-HT receptors, SERT) and enteric neural markers (NOS1, BDNF, TRPV1, GDNF) were analyzed using quantitative PCR (qPCR), Western blotting, and immunofluorescence staining. The gut microbiota composition was examined through 16S rDNA sequencing. Statistical analyses were conducted using GraphPad Prism, with significance set at P < 0.05. Leven PRO-CR significantly improved STC symptoms by reducing first defecation time, increasing stool frequency, fecal water content, and intestinal transit rate. We found that Leven PRO-CR restored colonic tissue integrity, enhanced ICC survival by upregulating c-Kit/SCF signaling, and reduced apoptosis. Leven PRO-CR upregulated TPH1 expression, increased 5-HT levels, and inhibited its degradation, thereby promoting intestinal motility. Leven PRO-CR also modulated NOS1, BDNF, TRPV1, and GDNF mRNA and protein expression, suggesting enhanced enteric nervous system function. 16S rDNA sequencing revealed increased microbial diversity and a restored balance of beneficial bacteria after Leven PRO-CR treatment, indicating the beneficial effects of Leven PRO-CR on balancing gut microbiota in STC. Overall, Leven PRO-CR alleviated slow-transit constipation potentially by enhancing 5-HT secretion, upregulating TPH1 channels, and restoring microbiota balance.
Curcumin mitigates testicular ischemia-reperfusion injury by suppressing NLRP3-mediated pyroptosis.
Hu Z, Wang J, Ning J … +1 more , Cheng F
Mol Immunol · 2025 Sep · PMID 40706257 · Publisher ↗
BACKGROUND: Testicular torsion results in damage by interrupting the blood supply. Nevertheless, the reestablishment of blood flow following testicular detorsion, a process known as testicular ischemia-reperfusion injury...
BACKGROUND: Testicular torsion results in damage by interrupting the blood supply. Nevertheless, the reestablishment of blood flow following testicular detorsion, a process known as testicular ischemia-reperfusion injury (IRI), often leads to further injury. Curcumin is a naturally occurring phenolic compound that has anti-inflammatory and antioxidant implications. It has been demonstrated to confer preventive implications in IRI between different organs. We propose ascertaining curcumin function in testicular IRI. METHODS: We created a mouse model to study testicular torsion/detorsion (T/D) and a germ cell model to study oxygen-glucose deprivation/reperfusion (OGD/R). The evaluation of testicular ischemia damage was conducted using histological staining. Testicular tissues were examined for the presence of reactive oxygen species (ROS) and pyroptosis-linked proteins employing western blot (WB), RT-qPCR, MDA, SOD assay kits, and immunohistochemistry analysis. Cell viability and cytotoxicity were measured via the Cell Counting Kit-8 (CCK-8) and LDH test kits. The amounts of inflammatory proteins were quantified employing ELISA, immunofluorescence, and immunoblotting methods. RESULTS: We observed that testicular IRI is involved in oxidative stress damage in cells, with an associated elevation in pyroptosis-linked proteins NLRP3 and caspase-1 (CASP-1) levels. Additionally, there is a rise in the inflammatory cytokines IL-1β and -18 levels. After treating with curcumin, we noted a significant inhibition of pyroptosis, particularly when the concentration was 20 μmol/L, where the inhibitory effect was most pronounced. Further investigation into the underlying mechanisms revealed that curcumin exerts its preventative implications against testicular IRI by targeting the NLRP3 pathway to suppress IRI-mediated pyroptosis. CONCLUSIONS: Curcumin mitigates testicular IRI-induced pyroptosis by modulating the NLRP3 signaling pathway, thereby alleviating cellular and tissue damage.
GDF15 activates the PI3K/AKT pathway to mediate macrophage M2 polarization to promote prostate cancer resistance to docetaxel.
Li R, Wu H, Ran F … +5 more , He Y, Sun H, Peng W, Wang Q, Li J
Mol Immunol · 2025 Sep · PMID 40674958 · Publisher ↗
Drug resistance in cancer treatment is a major challenge, and macrophage polarization plays a key role in the development of prostate cancer (PCa). Growth differentiation factor 15 (GDF15) is highly expressed in most can...
Drug resistance in cancer treatment is a major challenge, and macrophage polarization plays a key role in the development of prostate cancer (PCa). Growth differentiation factor 15 (GDF15) is highly expressed in most cancers and is induced during anticancer treatment. The aim of this study was to investigate the regulatory mechanism of GDF15 in macrophage polarization and resistance to docetaxel (DTX) in PCa patients. We collected clinical samples from PCa patients to evaluate the expression level of GDF15 and its correlation with M2-type macrophage polarization. In this study, CCK-8, RTqPCR, flow cytometry and western blotting were used to investigate the mechanisms by which GDF15 regulates macrophage M2 polarization and PCa chemotherapy resistance. The results showed that GDF15 was significantly upregulated in PCa samples and was closely related to the level of M2 macrophage polarization. Further experiments revealed that M2 macrophages synthesize GDF15, which is involved in the regulation of DTX resistance in PCa cells. Following knockdown of GDF15 expression in M2-type macrophages, we observed that the resistance of PCa cells to DTX was significantly attenuated. This regulatory mechanism was achieved mainly through the inhibition of the PI3K/AKT signaling pathway, preventing the M2 polarization of macrophages. In conclusion, the upregulation of GDF15 in M2 macrophages can activate the PI3K/AKT signaling pathway, enhancing the DTX resistance of PCa cells. These findings provide new insights and potential targets for treatment strategies against PCa chemotherapy resistance.
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.
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.
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.
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.
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