Molecular Immunology[JOURNAL]
Sun
200 papers
Inhibition of RNase L enhances the expression efficiency of mRNA-LNPs.
Nguyen HM, Cassaidy B, Collinge M … +5 more , Hickey JC, Li J, Arellano-Saab A, Kumpf SW, Thorn M
Mol Immunol · 2026 Feb · PMID 41564652 · Publisher ↗
mRNA-LNPs offer a promising platform for therapeutic protein expression, however, achieving efficient and sustained translation remains a significant challenge. One of the major barriers to mRNA-LNP efficacy is the activ...
mRNA-LNPs offer a promising platform for therapeutic protein expression, however, achieving efficient and sustained translation remains a significant challenge. One of the major barriers to mRNA-LNP efficacy is the activation of innate immune responses that recognize foreign RNA and suppress subsequent protein synthesis. Among these, the OAS-RNase L pathway, involved in degradation of cytoplasmic mRNA, plays a key role. This study examined the impact of RNase L and RNase L blockade on mRNA-LNP expression efficiency. In THP-1 cells, which express high endogenous levels of RNase L, both genetic ablation and pharmacological inhibition of RNase L led to a marked increase in protein expression. In contrast, HeLa cells, which exhibit low RNase L expression, showed minimal response to RNase L inhibition. In human peripheral blood mononuclear cells (PBMCs), RNase L inhibition also enhanced mRNA expression, while blocking other RNA sensors such as TLR7/8, RIG-I, TLR3, or MAVS, did not. Activation of the OAS-RNase L pathway may be driven by double-stranded secondary structure formed by therapeutic mRNA, resulting in mRNA recognition and degradation. RNase L acts as a key post-transcriptional regulator of mRNA stability and translation. Targeting this pathway offers a strategy to improve the performance of mRNA-based therapeutics.
Liquiritigenin regulates JAK/STAT3 and NF-κB signaling pathways to reduce colonic damage and barrier dysfunction caused by a high-salt diet.
Yan W, Wang L, Zhu W … +7 more , Liu X, Xu Z, Liu J, Ding J, Zhu M, Ma F, Dong Z
Mol Immunol · 2026 Feb · PMID 41558083 · Publisher ↗
It has been shown that a high-salt diet (HSD) significantly damages the colonic epithelial barrier, resulting in increased intestinal permeability, upset gut microbial balance, and generalized inflammation. Despite this,...
It has been shown that a high-salt diet (HSD) significantly damages the colonic epithelial barrier, resulting in increased intestinal permeability, upset gut microbial balance, and generalized inflammation. Despite this, effective therapeutic strategies to prevent HSD-induced intestinal damage remain limited. This study aims to explore the preventive properties and basic mechanisms of liquiritigenin (LG)，a natural flavonoid, against chronic colonic injury induced by prolonged HSD exposure. A murine model of chronic colitis was established by administering an 8 % NaCl diet, and LG therapy was used to evaluate how it affected the function of the intestinal barrier and allergic reactions. The development of pro- and anti-inflammatory cytokines (il-β, il-6, tnf-α, il-10, and inos) as well as important tight junction proteins (ZO-1, Claudin-3, and Occludin) was assessed. Furthermore, we investigated the molecular processes in vitro using normal colonic epithelial cell line NCM-460, with particular focus on the NF-κB and JAK/STAT3 signaling pathways. LG increased the expression of junction-binding proteins, greatly enhanced the intestinal wall integrity, and mitigated histopathological damage. Furthermore, it markedly attenuated excessive inflammatory responses both in vivo and in vitro. Mechanistically, LG suppressed the phosphorylation of key components within the pathways of JAK/STAT3 and NF-κB, thereby inhibiting downstream inflammatory signaling and epithelial cell injury. Collectively, these results demonstrate that liquiritigenin exerts protective effects against HSD-induced colonic damage by concurrently modulating the NF-κB and JAK/STAT3 pathways, highlighting its therapeutic potential for high salt-related intestinal disorders.
Liposome-mediated simvastatin in vaccine adjuvants: Its application and mechanism.
Chen Z, Xia Z, Chen L … +15 more , Nie Q, Gong W, Cao W, Wang X, Zou Y, Zhang S, Yang Y, Yang M, Yang J, Liu Y, Zhang L, Fang W, Chen Y, Zhao J, Meng Z
Mol Immunol · 2026 Feb · PMID 41539277 · Publisher ↗
To mitigate the APC cytotoxicity associated with simvastatin (a promising adjuvant candidate), we encapsulated this drug in liposomes to generate LIPO-SIM, and explored the potential and mechanism. Formulated via ethanol...
To mitigate the APC cytotoxicity associated with simvastatin (a promising adjuvant candidate), we encapsulated this drug in liposomes to generate LIPO-SIM, and explored the potential and mechanism. Formulated via ethanol injection and rotary evaporation, liposome-SIM was characterized for appearance, ζ-average, PDI, zeta potential, and encapsulation efficiency. C57BL/6 J mice were immunized with LIPO-SIM + OVA (0/21-day schedule), euthanized on day 28 to evaluate immunogenicity, safety, and antigen presentation mechanisms. In vitro, DC2.4 cells stimulated with liposome-SIM underwent RNA-Seq, metabolomics, and western blotting to clarify adjuvant mechanisms. Results showed liposome-SIM significantly increased anti-OVA IgG titers and cellular immunity, activated local lymph node macrophages/dendritic cells, and enhanced MHC-I presentation. In vitro, AMPK inhibition and NF-κB activation were observed. No organ toxicity or inflammatory storms were detected. Liposome-SIM enhances cellular immunity via the MHC-I pathway, with AMPK/NF-κB signaling as a potential key mechanism.
HSPH1 and DNAJB1 as potential key regulators in hepatic ischemia-reperfusion injury.
Wu S, Zhou W, Duo H … +7 more , You J, Chen Y, Du S, Ku N, Luo J, Liu Z, Ye Q
Mol Immunol · 2026 Feb · PMID 41534252 · Publisher ↗
Hepatic ischemia-reperfusion injury (HIRI) is a common and inevitable pathological event during liver transplantation and hepatectomy, which significantly impairs postoperative liver function recovery and patient prognos...
Hepatic ischemia-reperfusion injury (HIRI) is a common and inevitable pathological event during liver transplantation and hepatectomy, which significantly impairs postoperative liver function recovery and patient prognosis. However, the molecular and cellular mechanisms of HIRI have not been fully elucidated and further research is urgently needed. In recent years, the rapid development of bioinformatics analysis technology and the research method combining multi-dimensional data mining with experimental verification have become important strategies for exploring the mechanisms of complex diseases. Building on this, this study aims to screen and analyze the potential roles and mechanisms of key regulatory factors in the process of HIRI through systematic bioinformatics analysis and experimental verification, providing a basis for clarifying its pathogenesis and finding potential therapeutic targets. In this study, two transcriptome microarray datasets (GSE14951 and GSE7706) of human liver tissue were systematically analyzed, and candidate genes related to IRI were initially screened through differential expression analysis. Combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein-protein interaction (PPI) network construction and modular analysis were performed to identify potential key regulatory factors, ultimately highlighting HSPH1 and DNAJB1. Subsequently, based on a mouse liver IRI model, paired reperfusion tissue samples from clinical liver transplant patients, and an AML12 cell hypoxia/reoxygenation (H/R) model, the two genes were experimentally validated from multiple perspectives, including transcriptional expression, protein levels, and subcellular localization. A combination of quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) was employed to comprehensively evaluate their expression dynamics, subcellular distribution, and protein-protein interaction characteristics. Differential expression analysis identified 154 genes with consistent expression trends across the two datasets, which were significantly enriched in metabolic, stress response, inflammatory, and protein folding pathways. PPI network construction and module analysis further identified HSPH1 and DNAJB1 as core components of a heat shock protein interaction cluster. Validation using a mouse IRI model, paired reperfusion tissue samples from clinical liver transplant patients, and an AML12 cell hypoxia/reoxygenation (H/R) model demonstrated that both genes were significantly upregulated under IRI conditions, localized in the cytosol, and exhibited co-localization and physical interaction. Transcription factor prediction analysis suggested that STAT3 and NR1I2 might be involved in their transcriptional regulation. In conclusion, HSPH1 and DNAJB1 are co-expressed and physically interact in hepatic IRI, suggesting that they may be involved in the regulation of protein homeostasis and cellular stress responses related to liver IRI, providing important experimental evidence for a deeper understanding of the molecular characteristics of liver IRI.
NSUN2 aggravates M1 macrophage polarization in arthritis progression through m5C modification of CCL2.
He C, Zhang J, Deli G … +5 more , Zhao K, Liu L, Lai B, Hu M, He H
Mol Immunol · 2026 Feb · PMID 41506006 · Publisher ↗
BACKGROUND: Arthritis is an inflammatory disease characterized by multifactorial pathogenesis in joints or surrounding tissues. M1 macrophage polarization is a key pathological feature of arthritis, and m⁵C RNA modificat...
BACKGROUND: Arthritis is an inflammatory disease characterized by multifactorial pathogenesis in joints or surrounding tissues. M1 macrophage polarization is a key pathological feature of arthritis, and m⁵C RNA modification has been implicated in disease progression. This study aimed to elucidate the role of NSUN2, a writer of m⁵C modification, in modulating arthritis development. METHODS: LPS-stimulated RAW264.7 cell models and collagen-induced arthritis (CIA) rat models were established. M1 and M2 macrophage polarization was assessed by detecting cell surface markers and pro-inflammatory cytokines using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time PCR. Underlying mechanisms were investigated via methylated RNA immunoprecipitation (MeRIP), Co-immunoprecipitation (Co-IP), and Dual-Luciferase reporter assays. RESULTS: Downregulation of NSUN2 significantly inhibited M1 polarization and promoted M2 activation both in vitro and in vivo. NSUN2 enhanced m5C modification of CCL2, stabilized its mRNA expression, and facilitated its interaction with CCR2. Furthermore, NSUN2 activated the NF-κB signaling pathway in macrophages. Notably, inhibition of CCL2 activity abrogated the effects of NSUN2 on macrophage polarization. CONCLUSION: NSUN2 drives M1 macrophage polarization through m5C modification of CCL2, thereby exacerbating arthritis progression. Targeting NSUN2 may alleviate inflammatory responses, offering a novel therapeutic strategy for arthritis treatment.
Acupuncture alleviates premature ovarian insufficiency via Rictor/mTOR pathway in mice by stimulating the Guanyuan acupoint.
Luo Y, Chen Y, Huang S … +6 more , Zhu H, Zhao T, Feng S, Ma F, Ning Y, Wu J
Mol Immunol · 2026 Feb · PMID 41506005 · Publisher ↗
Acupuncture is a popular therapeutic therapy for premature ovarian insufficiency (POI). The specific effect and the underlying mechanism of Guanyuan acupoint on the ovarian function of POI model mice remain unclear. The...
Acupuncture is a popular therapeutic therapy for premature ovarian insufficiency (POI). The specific effect and the underlying mechanism of Guanyuan acupoint on the ovarian function of POI model mice remain unclear. The female C57BL6 mice were injected peritoneally with 12 mg/kg busulfan and 120 mg/kg cyclophosphamide to induce POI. The acupuncture intervention at Guanyuan acupoint was performed on the second day after the modeling. Vaginal smears were used to monitor the estrous cycle. The hematoxylin and eosin (H&E) staining was used to observe the morphological changes of ovarian tissue, and the TUNEL fluorescence staining assay was carried out to detect the apoptotic level of granulosa cells. The sex hormone levels were monitored as well. RNA sequencing was performed to select candidate gene which was regulated by acupuncture. Finally, the upstream lactating modification mechanism of Rictor was further investigated. The results showed that acupuncture at Guanyuan acupoint increased the number of vaginal exfoliated cells and inhibited the apoptosis of granulosa cell in POI model mice. Sex hormone levels indicated a marked decrease in AMH and E in POI group, with a concurrent significant rise in FSH levels. Furthermore, the Rictor/mTOR pathway was inactivated in POI model group, while was prominently activated by acupuncture at Guanyuan acupoint. Acupuncture intervened H3K18la to increase Rictor promoter activity in POI. In conclusion, acupuncture at Guanyuan acupoint increased body and ovarian weight, improved ovarian tissue morphology and structure, improved follicle development, and regulated ovarian function in POI model mice. This might be related to the activation of the Rictor/mTOR pathway.
Investigating the role of SMOX in rheumatoid arthritis.
Jiang Z, Zhang R, Han Y … +7 more , Sun R, Kong M, Zhang Y, Li J, Song G, Qiao L, Wang L
Mol Immunol · 2026 Jan · PMID 41485416 · Publisher ↗
Rheumatoid arthritis (RA) is pathologically marked by joint inflammation and damage. Although the association between spermidine and RA has been recognized, the precise contribution of spermine oxidase (SMOX)-the enzyme...
Rheumatoid arthritis (RA) is pathologically marked by joint inflammation and damage. Although the association between spermidine and RA has been recognized, the precise contribution of spermine oxidase (SMOX)-the enzyme catalyzing spermidine synthesis-to RA pathogenesis remains undefined. It's observed in this study that SMOX was responsible for inflammatory stimuli that its expression increased obviously when RA-associated fibroblast-like synoviocytes (FLSs) were challenged by inflammatory factors. Functionally, silencing SMOX could inhibit migration, invasion, and cytokine production, but induced apoptosis of RA-FLS. Moreover, inhibition of SMOX using JNJ-9350 yielded anti-inflammatory effects comparable to those achieved by gene silencing in RA-FLS. In vivo experiments demonstrated that JNJ-9350 could effectively reduce the severity of arthritis, minimize histopathological damage, and prevent bone erosion in collagen antibody-induced arthritis (CAIA) mice. The present results indicate that SMOX is implicated in the development of RA and suggest that targeting SMOX could be a novel treatment strategy.
An H₂S-releasing oridonin derivative protects HaCaT cells against metabolic stress via PI3K/AKT/Nrf2 signaling.
Lin L, Jia Y, Xue R … +4 more , Shi Y, Li D, Xu F, Chu C
Mol Immunol · 2026 Feb · PMID 41483658 · Publisher ↗
The chronic hyperglycemia and its-associated metabolic changes often lead to impaired wound healing, which seriously affects the quality of life of diabetic patients. Oxidative stress and apoptosis are key factors that i...
The chronic hyperglycemia and its-associated metabolic changes often lead to impaired wound healing, which seriously affects the quality of life of diabetic patients. Oxidative stress and apoptosis are key factors that impede epidermal cell proliferation and migration and delay wound healing. The aim of this study was to investigate the protective effect of a novel hydrogen sulfide (HS)-releasing oridonin derivative (OAc-Ph-ADT) on epidermal HaCaT cells against a high-glucose and high-fat environment in vitro. Mechanistic studies showed that OAc-Ph-ADT exerted its antioxidant effects by activating the PI3K/AKT/Nrf2 signaling pathway. Specifically, it increased PI3K and phosphorylated-AKT expression, and promotes Nrf2 nuclear translocation, which in turn enhances the mRNA and protein expression of downstream antioxidant factors (HO-1, SOD2 and NQO1). In addition, OAc-Ph-ADT significantly reduced apoptosis by inhibiting the decrease in mitochondrial membrane potential and decreasing the expression of apoptosis-related proteins (Bax, Cleaved-Caspase 3/9). It was also observed that OAc-Ph-ADT up-regulated the expression of cystathionine β-synthase (CBS) via Nrf2, which further promoted the synthesis of endogenous HS, resulting in positive feedback regulation. In summary, this paper elucidated through systematic in vitro experiments that OAc-Ph-ADT has a protective effect against epidermal cell damage in a high-glucose and high-fat environment, revealing its potential as a candidate molecule for diabetic wound treatment, and this novel HS-releasing oridonin derivative has a potential application as a diabetic wound healing promoter.
Hippo signaling as a therapeutic switch for T cell functions and tumor immunity.
Fan J, Riaz F, Pan F
Mol Immunol · 2026 Feb · PMID 41483657 · Publisher ↗
The Hippo signaling pathway is a fundamental regulator of organ growth, tissue regeneration, and cellular homeostasis, with far-reaching implications in cancer biology and immunology. Dysregulation of this pathway, parti...
The Hippo signaling pathway is a fundamental regulator of organ growth, tissue regeneration, and cellular homeostasis, with far-reaching implications in cancer biology and immunology. Dysregulation of this pathway, particularly through its downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), is closely associated with oncogenic transformation and the establishment of an immunosuppressive tumor microenvironment (TME). This review discusses current knowledge on the multifaceted roles of Hippo signaling in cancer, focusing on its interactions with T cell-mediated immunity and mechanisms of tumor immune regulation. Aberrant YAP/TAZ activation enhances cancer cell proliferation, remodels the TME, and reprograms immune responses to favor tumor growth and immune evasion. The review explores how modulation of Hippo pathway components influences both tumor progression and immune cell function, highlighting its central role in shaping anti-tumor immunity. Furthermore, the therapeutic potential of targeting YAP/TAZ signaling is discussed in the context of advancing precision medicine and improving immunotherapeutic outcomes. Collectively, this work highlights the Hippo signaling cascade as both a key driver of tumorigenesis and a crucial regulator of immune modulation. A comprehensive understanding of its molecular interactions with T cells and the TME will support the development of innovative YAP/TAZ-targeted strategies that integrate molecular signaling and immune modulation, offering new directions for effective cancer therapy.
Formononetin in Jiawei Qihuangyin inhibits podocyte epithelial-mesenchymal transition and ameliorates diabetic nephropathy via SIRT1/NF-κB axis.
Li H, Ke J, Zhou Y … +4 more , Chen H, Wu X, Liu H, Li J
Mol Immunol · 2026 Feb · PMID 41483656 · Publisher ↗
BACKGROUND: Traditional Chinese medicine (TCM) has shown great promise in treating diabetic nephropathy (DN). However, the key targets and mechanisms underlying the therapeutic effects of the active ingredients of modifi...
BACKGROUND: Traditional Chinese medicine (TCM) has shown great promise in treating diabetic nephropathy (DN). However, the key targets and mechanisms underlying the therapeutic effects of the active ingredients of modified prescription Jiawei Qihuangyin (JWQHY) remain unclear. METHODS: Network pharmacology analysis was employed to identify potential targets of JWQHY in DN. Protein-protein interaction (PPI) and TCM component-target networks were constructed, and KEGG pathway enrichment analysis was performed to determine key therapeutic targets and signaling pathways. Molecular docking suggested an interaction between the major active compound formononetin (FMN) and the central target silent information regulator 1 (SIRT1), which was experimentally validated using cellular thermal shift assay. SIRT1 expression in podocytes was assessed by qRT-PCR and western blotting (WB). Cell viability (CCK-8), apoptosis (flow cytometry), and proinflammatory cytokine secretion (ELISA) were measured to evaluate podocyte injury. The acetylation level of NF-κB p65 and epithelial-mesenchymal transition (EMT)-related proteins were analyzed by WB. In vivo, a DN rat model was established to assess the therapeutic efficacy of JWQHY through biochemical urine analysis, histopathological examination (HE staining), and WB detection of SIRT1, acetylated NF-κB p65, and EMT markers. RESULTS: Network pharmacology identified 52 potential overlapping targets of JWQHY in DN, primarily associated with the NF-κB pathway. Among these, SIRT1 was predicted and experimentally confirmed as the main target of FMN. In a high-glucose-induced podocyte injury model, FMN upregulated SIRT1 expression, promoted NF-κB p65 deacetylation, and inhibited podocyte EMT. Consistently, FMN treatment improved renal function, reduced podocyte injury, and modulated SIRT1/NF-κB signaling in DN rats. CONCLUSION: JWQHY exerts therapeutic effects in diabetic nephropathy by modulating the SIRT1/NF-κB signaling axis through its active compound formononetin, thereby inhibiting podocyte EMT. These findings provide mechanistic insight into the pharmacological basis of FMN and support its clinical potential in DN treatment.
CXCL2-TLR4 axis activates NETs by accelerating autophagy through ATG7 to promote the progression of idiopathic interstitial pneumonia.
He J, Li J, Bai M … +1 more , Yang J
Mol Immunol · 2026 Jan · PMID 41443150 · Publisher ↗
OBJECTIVE: This study aimed to elucidate the molecular mechanisms through which CXCL2 contributes to the pathogenesis of idiopathic interstitial pneumonia (IIP). METHODS: Neutrophils were isolated, and the formation of n...
OBJECTIVE: This study aimed to elucidate the molecular mechanisms through which CXCL2 contributes to the pathogenesis of idiopathic interstitial pneumonia (IIP). METHODS: Neutrophils were isolated, and the formation of neutrophil extracellular traps (NETs) was assessed after CXCL2 treatment. Cellular concentrations of cell-free DNA (cf-DNA) were quantified via a cf-DNA/NET kit. Additionally, an enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of IL-6, TNF-α, and LL-37. Western blot analysis was used to measure the levels of LC3-II, LC3-I, citrullinated histone H3 (citH3), myeloperoxidase (MPO), and elastase. Immunohistochemistry was conducted to measure cit H3 levels. Pathological alterations in the lung tissue were examined via microscopic hemosiderin and eosin staining. RESULTS: CXCL2 treatment significantly increased the cellular expression levels of cf-DNA, IL-6, TNF-α, and LL-37, as well as cit H3 and MPO, which are markers of NETs. Furthermore, CXCL2 treatment induced a substantial increase in cellular autophagy. Additionally, CXCL2 treatment led to marked upregulation of TLR4 expression and further elevation of autophagy levels, accompanied by increases in cf-DNA, IL-6, TNF-α, and LL-37 expression. Inhibition of TLR4 expression significantly reduced the levels of these factors. Moreover, the CXCL2-induced upregulation of cf-DNA, IL-6, TNF-α, LL-37, cit H3, and MPO was notably suppressed following the knockdown of ATG7. In IIP murine models, there was a significant upregulation of cf-DNA, IL-6, TNF-α, and LL-37, as well as an increase in cit H3 and MPO expression. Lung tissue analysis revealed inflammatory cell infiltration, alveolar wall thickening, tissue congestion, and edema. Inhibition of CXCL2 and TLR4 expression significantly ameliorated these pathological changes. CONCLUSIONS: The CXCL2TLR4 axis may facilitate NET activation by promoting autophagy via ATG7, thereby contributing to IIP progression.
Silence of circPLK1 inhibits NSCLC progression by regulating the miR-1294/SLC16A9 axis.
Li C, Yang Y, Li Q … +4 more , Wang G, Tao T, Li L, Sang H
Mol Immunol · 2026 Jan · PMID 41443149 · Publisher ↗
BACKGROUND: Non-small cell lung cancer (NSCLC) is the malignancy with the highest mortality worldwide. Circular RNA polo-like kinase 1 (circPLK1) is a circular RNA that involved in cancer progression. However, the role o...
BACKGROUND: Non-small cell lung cancer (NSCLC) is the malignancy with the highest mortality worldwide. Circular RNA polo-like kinase 1 (circPLK1) is a circular RNA that involved in cancer progression. However, the role of circPLK1 in NSCLC requires further investigation. METHODS: The expression of circPLK1 in NSCLC cells was measured by using qRT-PCR. Bioinformatics analysis was performed to identify miRNAs that bind to circPLK1 and the target mRNAs of these miRNAs. Cell viability, proliferation, apoptosis, migration, and invasion were assessed using CCK-8, colony formation, flow cytometry, and Transwell assays, respectively. Protein expression was evaluated by western blotting. Xenograft models were established to verify the regulatory role of circPLK1 in the miR-1294/SLC16A9 axis. RESULTS: circPLK1 was upregulaterd in NSCLC cells. Silencing circPLK1 markedly inhibited cell viability, proliferation, migration, and invasion, while accelerating apoptosis in NSCLC cells. circPLK1 acted as a sponge for miR-1294 and promoted SLC16A9 expression in NSCLC cells. Knockdown of circPLK1 suppressed tumor growth in NSCLC by regulating the miR-1294/SLC16A9 axis. CONCLUSION: circPLK1 silence inhibited the proliferation, migration, and invasion of NSCLC cells by regulating the miR-1294/SLC16A9 axis.
Restoring NR4A3 function in neutrophils alleviates sepsis by limiting NF-κB-dependent NETs formation and organ damage.
Li S, Liu C, Wu C … +1 more , Liu Z
Mol Immunol · 2026 Jan · PMID 41443148 · Publisher ↗
BACKGROUND: Sepsis, a life-threatening condition, involves excessive neutrophil extracellular traps (NETs) contributing to organ damage. The role of orphan nuclear receptor NR4A3 in modulating neutrophil NETosis via NF-κ...
BACKGROUND: Sepsis, a life-threatening condition, involves excessive neutrophil extracellular traps (NETs) contributing to organ damage. The role of orphan nuclear receptor NR4A3 in modulating neutrophil NETosis via NF-κB during sepsis is poorly understood. This study aimed to elucidate NR4A3's function and therapeutic potential. METHODS: Single-cell RNA sequencing analysis was performed using GSE175453 and GSE167363 from GEO database, involving PBMCs from septic patients and controls. In vitro, ATRA-differentiated HL-60 neutrophils with NR4A3 overexpression were LPS-stimulated. In vivo, a cecal ligation and puncture (CLP) sepsis mouse model received AAV-mediated NR4A3 overexpression. Key readouts included NR4A3 expression, NF-κB activation, NETs markers (NE, CitH3, PADI4, MPO-DNA), inflammatory cytokines (TNF-α, IL-1β, IL-6), ROS generation, and intestinal tissue pathology. RESULTS: scRNA-seq analysis revealed significant NR4A3 downregulation in neutrophils from septic patients. In vitro, NR4A3 overexpression in neutrophils significantly attenuated LPS-induced NF-κB (p65) activation, NETs formation, inflammatory cytokine production, and ROS generation. In vivo, AAV-mediated NR4A3 overexpression in CLP-induced septic mice ameliorated intestinal inflammation, suppressed p65 phosphorylation and NETs-related markers in the intestine, and reduced systemic inflammatory cytokine levels. CONCLUSION: Our findings demonstrate that NR4A3 exerts a protective role in sepsis by inhibiting the NF-κB signaling pathway in neutrophils, thereby suppressing excessive NETs formation and the associated inflammatory cascade. Thus, NR4A3 represents a promising therapeutic target for mitigating NET-driven pathology in sepsis.
Indole-3-propionic acid exerts radio-protective effects by modulating Wnt1/STAT3 pathway to alleviate oxidative stress and neuroinflammation in microglia.
Si Y, Zhang B, Wei J … +3 more , Li M, Liu Y, Ma H
Mol Immunol · 2026 Jan · PMID 41435624 · Publisher ↗
Radiation-induced delayed brain injury (RIBI) refers to structural and functional brain alterations that develop several months to years after exposure to ionizing radiation (IR). Microglia activation-mediated neuroinfla...
Radiation-induced delayed brain injury (RIBI) refers to structural and functional brain alterations that develop several months to years after exposure to ionizing radiation (IR). Microglia activation-mediated neuroinflammation, as well as oxidative stress, constitutes a key factor contributing to RIBI. Indole-3-propionic acid (IPA) is an indole metabolite specifically produced by the tryptophan metabolism of gut microbiota. It can cross the blood-brain barrier and modulate the central nervous system (CNS). In order to explore the protective mechanism of IPA on IR-induced cerebral function, we studied the effect of IPA on the activation of BV2 microglia in vitro. The experimental results show that IPA can suppress the oxidative stress and inflammation of microglia, which is represented as upregulating the expression of antioxidant genes (Hmox1, Ho-1, and Nqo1), and reducing the mRNA levels of pro-inflammatory factors (Tnf-α, Il-6, Inos, and Nox2). This protective effect may be related to the inhibition of Wnt1 expression and STAT3 phosphorylation (p-STAT3 Y705; p = 0.0008) in microglia. Additionally, it was found that IPA could alleviate the IR-induced neuroinflammation and synaptic damage of mice, as evidenced by reduced serum TNF-α and IL-6 levels and widened postsynaptic density (PSD) thickness (p = 0.0239). Collectively, this study provides novel insights into the potential application of IPA in the therapeutic intervention of radiation-induced brain injury.
Isoimperatorin inhibits cell proliferation and induces apoptosis via regulating PI3K/AKT pathway in acute lymphoblastic leukemia.
Xiao J, Wang Y
Mol Immunol · 2026 Jan · PMID 41418420 · Publisher ↗
OBJECTIVES: This study aims to explore whether isoimperatorin (ISOIM) regulates the malignant phenotype of T‑cell acute lymphoblastic leukemia (T-ALL) cells through the PI3K/AKT pathway and programmed cell death ligand-1...
OBJECTIVES: This study aims to explore whether isoimperatorin (ISOIM) regulates the malignant phenotype of T‑cell acute lymphoblastic leukemia (T-ALL) cells through the PI3K/AKT pathway and programmed cell death ligand-1 (PD-L1). METHODS: Through in vitro experiments, ISOIM on T-ALL cell proliferation and apoptosis was evaluated using the cell counting kit-8 and EdU assays, flow cytometry, and TUNEL staining. Network pharmacology, molecular docking, and functional enrichment analyses were conducted to analyze the underlying mechanisms of ISOIM. Changes in apoptosis-related proteins, PD-L1 protein, and PI3K/AKT pathway-related proteins were assessed by western blotting. RESULTS: ISOIM inhibited T-ALL cell proliferation, promoted apoptosis, decreased Bcl-2 levels, and increased C-caspase-3 and Bax levels. KEGG and GO enrichment analyses indicated that the overlapping targets between ISOIM and ALL were related to the PD-1 checkpoint and PI3K/AKT pathway. Molecular docking analysis showed good binding between ISOIM and PIK3CA (also known as PI3K). ISOIM reduced PD-L1, p-PI3K, p-AKT, and p-mTOR levels. Moreover, the PI3K/AKT pathway activator 740 Y-P reversed the inhibitory effect of ISOIM on PD-L1 expression and the malignant behavior of T-ALL cells. CONCLUSIONS: ISOIM inhibited the malignant behavior of T-ALL cells and reduced PD-L1 levels by suppressing the PI3K/AKT pathway. This study provides a theoretical basis for developing novel treatment strategies for ALL.
Increased TNF-α in SJS/TEN induced by PD-1 inhibitors supports the combination therapy of etanercept and systemic corticosteroids.
Xiong H, Shen Z
Mol Immunol · 2026 Jan · PMID 41418419 · Publisher ↗
BACKGROUND: Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN) induced by programmed cell death protein 1 (PD-1) inhibitors is a life-threatening condition. Although the exact pathogenesis remains unknown, i...
BACKGROUND: Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN) induced by programmed cell death protein 1 (PD-1) inhibitors is a life-threatening condition. Although the exact pathogenesis remains unknown, its treatment mainly relies on high-dose systemic corticosteroids. Given the vital role of tumor necrosis factor-alpha (TNF-α) in classic SJS/TEN, this study sought to investigate the expression of TNF-α and evaluate the effectiveness and safety of combination therapy of etanercept and systemic corticosteroids in PD-1 inhibitor-induced SJS/TEN. METHODS: PD-1 inhibitor-induced SJS/TEN patients (n = 5) meeting diagnostic criteria, including skin biopsy-confirmed full-thickness epidermal necrosis with PD-1 as the sole culprit drug by ALDEN scoring, were enrolled in the study. Single-cell RNA sequencing (scRNA-seq) was conducted on lesional skin from one index patient (blister, erythema, and normal sites). Immunofluorescence staining for TNF-α was performed on samples from all five patients. Finally, a combination therapy of etanercept and systemic corticosteroids was administered to the patients, and the re-epithelization time, corticosteroid treatment duration, and prednisone cumulative dose were analyzed. RESULTS: scRNA-seq revealed significantly increased TNF-α expression in lesional skin compared with normal skin (p < 0.05), primarily from macrophages, which represented the predominant cell population in the lesion. Immunofluorescence confirmed TNF-α elevation in all five patients (p < 0.05). Besides, combination therapy resulted in rapid re-epithelialization (5.75 ± 1.48 days), a shorter steroid duration (17.75 ± 2.86 days), and reduced cumulative prednisone use (9.83 ± 3.71 mg/kg). No treatment-related severe adverse events occurred. One patient subsequently received a PD-1 inhibitor after recovery and tolerated the re-treatment without complication. CONCLUSIONS: Our findings demonstrated upregulation of TNF-α expression in PD-1 inhibitor-induced SJS/TEN, mainly derived from macrophages. The combination of etanercept and systemic corticosteroids exhibits huge potential for treating this patient population.
The genetic characteristics of Pahepcidin1 and Pahepcidin2 in silver pomfret (Pampus argenteus) and their antibacterial functions in innate immunity.
Fang Q, Wang R, Liu X … +5 more , Wang Y, Xie Q, Guo C, Yuan M, Wang X
Mol Immunol · 2026 Jan · PMID 41418418 · Publisher ↗
Hepcidins are a class of cysteine-rich antimicrobial peptides that exert significant impacts in response to a variety of pathogens. In this study, two hepcidins were identified from silver pomfret (Pampus argenteus), nam...
Hepcidins are a class of cysteine-rich antimicrobial peptides that exert significant impacts in response to a variety of pathogens. In this study, two hepcidins were identified from silver pomfret (Pampus argenteus), namely Pahepcidin1 and Pahepcidin2. Our findings revealed that Pahepcidin1 consists of a 267 open reading frame (ORF) encoding 91 amino acids, while Pahepcidin2 consists of 246 bp ORF encoding 81 amino acids. Sequence comparison between Pahepcidins and other homologous genes demonstrated the presence of eight conserved cysteines in the C-terminus region of Pahepcidin1 and six cysteine residues in the C-terminus region of Pahepcidin2. Phylogenetic analysis indicated that both Pahepcidin1 and Pahepcidin2 clustered with other fish homologues, respectively. The results of tissue-specific expression analysis showed that Pahepcidins exhibited the highest expression level in the liver; moreover, the expression level of Pahepcidin1 in silver pomfret liver cells (PaL cells) was also significantly increased after stimulation with lipopolysaccharide (LPS), polyinosinic-polycytidylic acid (poly I:C), and Staphylococcus aureus (S. aureus). Meanwhile, this study verified the antibacterial function of recombinant Pahepcidin1, and the results indicated that it possessed broad antibacterial activity against both Gram-positive bacteria (S. aureus) and Gram-negative bacteria (Edwardsiella tarda). In addition, the overexpression of Pahepcidin1 could significantly alter the transcriptional levels of key genes in the NF-κB pathway and downstream immune-related genes. In vivo validation via Vibrio parahaemolyticus challenge showed that Pahepcidin1 expression in silver pomfret liver was significantly upregulated at 3 h and peaked at 6 h, then downregulated to below the baseline from 12 h to 48 h. These results suggested that Pahepcidin1 might play an essential role in the innate immune system modulation of silver pomfret, providing valuable insights into understanding the antimicrobial immune mechanism of this species.
Hypoxic conditioning induced by CoCl enhanced the therapeutic effects of mesenchymal stem cell-derived exosomes on oxazolone-induced atopic dermatitis-like skin lesions in BALB/c mice.
Kim JW, Lee HJ, Chang PS … +2 more , Lee JM, Kim JC
Mol Immunol · 2026 Jan · PMID 41411738 · Publisher ↗
Atopic dermatitis (AD) is a chronic skin disease characterized by inflammation and disruption of the skin barrier. It is normally treated using moisturizers and steroids; however, these are palliatives and do not serve a...
Atopic dermatitis (AD) is a chronic skin disease characterized by inflammation and disruption of the skin barrier. It is normally treated using moisturizers and steroids; however, these are palliatives and do not serve as a therapy. Mesenchymal stem cells (MSCs) are tissue stem cells with immunomodulatory activities, and exosomes reflect the physiologies of producer cells. Therefore, the use of MSCs and exosomes with their immunomodulatory activities is emerging as a new method to treat AD. Here, we used cobalt chloride (CoCl) to induce hypoxic conditioning, and tested the therapeutic efficacy of exosomes derived from CoCl-treated MSCs in treating AD. In vitro, the exosomes derived from CoCl-treated MSCs increased the proliferation of HaCaT cells and decreased inflammatory cytokine levels. In the oxazolone-induced chronic AD mouse model, the exosomes derived from CoCl-treated MSCs reduced ear thickness, restored the skin barrier, and reduced immune cell infiltration and inflammatory markers. These data indicated that hypoxic conditioning induced by the CoCl treatment enhanced the therapeutic efficacy of exosomes derived from MSCs, suggesting that these exosomes can be used to alleviate the symptoms of AD. Given the current AD treatment landscape dominated by biologics and JAK inhibitors, our approach may serve as a steroid-sparing, biologic-agnostic adjunct or alternative, leveraging the safety and manufacturability of cell-free therapy.
The role of miR-3188-mediated transcriptional activation of IL-7Rα in tumor immunotherapy research.
Wan D, Liang X, Liang F … +3 more , Zhu M, Zhang C, Zhang S
Mol Immunol · 2026 Jan · PMID 41406630 · Publisher ↗
BACKGROUND: Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach for disseminated malignancies. However, ex vivo-expanded tumor-infiltrating lymphocytes (TI...
BACKGROUND: Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach for disseminated malignancies. However, ex vivo-expanded tumor-infiltrating lymphocytes (TIL) often rapidly progress to a state of functional exhaustion or suppression within the tumor microenvironment. Interleukin-7(IL-7) not only supports the survival of T-lymphocyte in vivo but also induces vigorous expansion of naïve and memory T lymphocytes in vitro. Upregulating the expression of interleukin-7 receptor alpha (IL-7Rα) helps T cells restore their responsiveness to IL-7 signaling, aids in their survival, and enables them to regain anti-tumor activity. METHODS: Firstly, we utilized databases to analyze the expression changes of CD127 in different tumor tissues, clarifying the correlation between its expression changes and patient prognosis. Subsequently, we collected clinical patient samples to validate the expression changes of CD127 in tumor-infiltrating T cells. We also simulated the tumor microenvironment through in vitro co-culture to explore the impact of tumor cells on the expression of CD127 on the surface of T cells. After then, we screened for miRNAs that are complementary to the sequence of the TATA box region in the CD127 promoter and employed a CD127 promoter driven dual-luciferase reporter system to identify the specific miRNA capable of upregulating CD127 expression. Finally, we analyzed the effects of miRNA-mediated upregulation of CD127 on T cell function. RESULTS: Bioinformatics analysis and clinical validation both confirmed decreased IL-7Rα expression in tumors. Moreover, in clinical samples, IL-7Rα and miR-3188 expression levels showed concordant changes and a positive correlation. miR-3188 can upregulate the expression level of IL-7Rα by specifically targeting the TATA-box region of CD127 promoter. Utilizing miR-3188 to upregulate IL-7Rα expression can facilitate T cell survival, promote the development of memory T cells and enhance the secondary response and tumor-killing capacity of T cells. CONCLUSION: Our findings reveal a novel mechanism of IL-7Rα regulation and propose a potential strategy to improve the persistence and functionality of T cells for ACT.
Construction of Enterococcus faecium-mediated ExoU vaccine and its protective effect in mice challenged with Pseudomonas aeruginosa.
Yang F, Yang S, Ou X … +3 more , He A, Yang X, Li W
Mol Immunol · 2026 Jan · PMID 41380468 · Publisher ↗
BACKGROUND: Pseudomonas aeruginosa (Pa) is an opportunistic pathogen and an important cause of nosocomial infections, and its antimicrobial resistance is a major therapeutic challenge. DNA vaccination is an attractive an...
BACKGROUND: Pseudomonas aeruginosa (Pa) is an opportunistic pathogen and an important cause of nosocomial infections, and its antimicrobial resistance is a major therapeutic challenge. DNA vaccination is an attractive antigen-specific immunotherapy approach. METHODS: In this study, we used the most acutely cytotoxic effector exoenzyme U (ExoU) released by Pa as the specific antigen and the safe and reliable Enterococcus faecium (Ef) as the expression vector, to construct the recombinant Ef-ExoU vaccine. The immune protection and humoral and cellular immune responses of the DNA vaccine were evaluated in mice by oral gavage. RESULTS: We found that the Ef-ExoU vaccine significantly reduced lung bacterial load and lung inflammatory cytokines (IL-6, TNF-α), probably by inducing higher levels of IgG and spleen CD4 T cell proliferation, indicating the induction of a mixed Th1 and Th2 immune response. CONCLUSIONS: This study suggests that Ef-ExoU is a promising subunit vaccine candidate and provides a new strategy for the prevention and treatment of Pa infection.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe