Molecular Immunology[JOURNAL]
Sun
200 papers
Immunological pathways triggered by Porphyromonas gingivalis in periodontitis: New insights into molecular mechanisms.
Ferenc K, Bożek A, Gawron K
Mol Immunol · 2026 Jan · PMID 41349496 · Publisher ↗
Periodontitis (PD) is one of the most common chronic inflammatory diseases worldwide. One of the keystone causative agents of PD is considered an anaerobic, Gram-negative, opportunistic oral bacterium - Porphyromonas gin...
Periodontitis (PD) is one of the most common chronic inflammatory diseases worldwide. One of the keystone causative agents of PD is considered an anaerobic, Gram-negative, opportunistic oral bacterium - Porphyromonas gingivalis, which has evolved sophisticated mechanisms to evade host immune responses, thus contributing to persistent inflammation and periodontal tissue destruction. As reported in the literature, P. gingivalis interacts with various host receptors and manipulates key immunological signaling pathways, including Toll-like receptor (TLR) signaling, the complement system, and PI3K-AKT signaling. By disrupting these pathways, it subverts host defense mechanisms, promotes dysbiosis, and exacerbates PD progression. Furthermore, emerging evidence suggests, that P. gingivalis infections may have systemic implications, linking PD to conditions, such as, neurodegenerative disorders, rheumatoid arthritis, and cardiovascular diseases. We discussed in this review the molecular mechanisms by which P. gingivalis manipulates key signaling pathways of inflammation and provided a comprehensive review of the intricate molecular interactions between P. gingivalis and host immune responses, emphasizing the ability of this oral pathogen to alter fundamental signaling cascades. Continued exploration of the molecular interplay between this pathogen and the host immune system will not only enhance our knowledge of PD but may also have broader implications for understanding pathogenetic events of associated systemic inflammatory conditions.
Mitochondria in pyroptosis: Mechanisms and implications.
Eldakhakhny BM, Abdulaal WH, Khan J … +7 more , Ajoolabady A, Pratico D, Bahijri S, Tuomilehto J, Borai A, Kim B, Ren J
Mol Immunol · 2026 Jan · PMID 41344083 · Publisher ↗
Pyroptosis is an inflammatory, necrotic, and lytic form of programmed cell death, involving activation of inflammasome complexes, inflammatory caspases, and the cleavage of gasdermins. Gasdermins are a large family of po...
Pyroptosis is an inflammatory, necrotic, and lytic form of programmed cell death, involving activation of inflammasome complexes, inflammatory caspases, and the cleavage of gasdermins. Gasdermins are a large family of pore-forming proteins with critical implications in key cellular processes and inflammatory disease contexts. These gasdermins subsequently oligomerize to form pores in the plasma membrane, releasing cellular contents and inflammatory mediators. Mechanistically, pyroptosis can occur via either caspase-1-dependent canonical pathway or the caspase-1-independent non-canonical pathway, both ultimately resulting in similar forms of pyroptotic cell death. While the underlying mechanisms of pyroptosis are broad and complex, certain key processes simplify the understanding of these mechanisms. One such critical process is the role of mitochondria and mitochondrial dysfunction in mediating pre-pyroptotic signaling. This review aims to provide a brief overview of the general mechanisms of pyroptosis, followed by a discussion of the latest findings on the functional and regulatory roles of mitochondria in pyroptosis. Moreover, we aimed to discuss and decipher emerging concepts such as the interaction between gasdermin D and cardiolipin, the role of mitochondrial DNA and its associated signaling pathways, as well as perspectives on the clinical relevance of these findings in conditions like sepsis, cardiotoxicity, and other diseases.
Loss of GNB2L1 promotes expansion of CD74 dendritic cells and contributes to development of diabetic foot ulcers.
Wang Y, Hang B, Liu H … +1 more , Cheng C
Mol Immunol · 2026 Jan · PMID 41344082 · Publisher ↗
Refractory diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation both locally and systemically. GNB2L1 has been reported to be associated with wound healing in diabetic rats, but the specific me...
Refractory diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation both locally and systemically. GNB2L1 has been reported to be associated with wound healing in diabetic rats, but the specific mechanism by which it acts has not been explored. scRNA-seq data from foot skin samples of three diabetic patients without DFU (non-DFU) and four diabetic patients with non-healing DFU (DFU) were downloaded from the GSE165816 dataset and analyzed. Twenty-five different cell clusters and fourteen cell types were identified, and the dendritic cell (DC) cluster was identified as a meaningful cell type. Skin wound tissues from 36 patients with DFU and 30 diabetic patients without DFU were collected. Based on gene signature analysis of the DC cluster, we identified a CD74 DC subset with a high proportion in the DFU group in clinical samples. Moreover, enrichment analysis of differentially expressed genes in the DC cluster revealed that they were mainly related to infection, immune response, and ATP synthesis. GNB2L1 was identified as the most significantly down-regulated gene, and its expression level was negatively correlated with the wound healing time in DFU patients. A full-thickness dorsal wound model in db/db mice was established, and GNB2L1 upregulation promoted wound healing in db/db mice. CD74 and CD74 DCs were isolated from blood samples of the above patients. CD74 upregulation promoted mitochondrial damage in DCs, which was reversed by GNB2L1 overexpression. In conclusion, GNB2L1 deficiency promotes CD74 dendritic cell expansion and diabetic foot ulcer development.
Fecal metabolomics in Crohn's disease reveal N-Acetylglutamine as a Th17/Treg modulator.
Han M, Dong X, Zhao R … +6 more , Hu X, Li D, Yan X, Liu Y, Du Q, Li M
Mol Immunol · 2026 Jan · PMID 41337940 · Publisher ↗
The gut microbiota is widely recognized as a key component in the pathogenesis of inflammatory bowel disease (IBD), and one of its primary modes of interaction with the host occurs via metabolites. Studies have confirmed...
The gut microbiota is widely recognized as a key component in the pathogenesis of inflammatory bowel disease (IBD), and one of its primary modes of interaction with the host occurs via metabolites. Studies have confirmed that gut microbiota dysbiosis affects immune maturation, immune homeostasis, host energy metabolism, and the maintenance of mucosal integrity. However, the specific metabolites that influence the differentiation of mucosal CD4 T cells remain insufficiently elucidated. This study aimed to identify and validate unknown metabolites capable of affecting the differentiation of CD4 T cell subsets by characterizing changes in fecal metabolites between IBD patients and non-IBD controls. Using untargeted metabolomics, we quantitatively detected a total of 1480 metabolites in positive ion mode and 1178 metabolites in negative ion mode. Regression analysis results showed that N-Acetylglutamine was significantly downregulated in IBD patients and was identified as a key differential metabolite. Further in vitro functional experiments confirmed that this metabolite could directly regulate the differentiation balance of CD4 T cells, specifically inhibiting the differentiation of pathogenic Th17 (pTh17) cells while promoting the generation of Treg. This study verifies the critical role of the metabolite N-Acetylglutamine in regulating the Treg/pTh17 cell balance, providing a theoretical basis for its potential as a therapeutic target for IBD.
Coxsackievirus B3 regulates macrophage polarization through ANXA3 to promote the development of myocarditis.
Chen Y, Liu X, Meng L … +5 more , Li B, Su Z, Jiang L, Wu Y, Zhang X
Mol Immunol · 2026 Jan · PMID 41337939 · Publisher ↗
BACKGROUND: Viral myocarditis (VMC) is a common inflammatory disease in children that is caused mainly by Coxsackievirus B3 (CVB3) infection. M1 macrophage polarization is a key pathological event in the progression of C...
BACKGROUND: Viral myocarditis (VMC) is a common inflammatory disease in children that is caused mainly by Coxsackievirus B3 (CVB3) infection. M1 macrophage polarization is a key pathological event in the progression of CVB3-induced myocarditis, and annexin 3 (ANXA3) plays an important role in the process of macrophage activation. Therefore, this study aimed to investigate the function of ANXA3 in CVB3-induced myocarditis and macrophage polarization. METHODS: CVB3-challenged mice were used to establish a CVB3-induced myocarditis model, and the polarization of RAW264.7 cells was induced by CVB3 infection. The expression of genes and proteins was detected by RT-qPCR, western blotting, immunohistochemistry, immunofluorescence, and ELISA. The pathological lesions in the cardiac tissue were detected by HE staining. Serum levels of myocardial injury markers were detected using kits. RESULTS: We found that ANXA3 expression was increased in VMC. ANXA3 knockdown hindered the progression of CVB3-induced VMC, as manifested by increased body weight, reduced inflammatory cell infiltration in the heart, and decreased serum levels of myocardial injury markers (LDH, CK, CK-MB and cTnI). ANXA3 knockdown also inhibited the M1 polarization of CVB3-infected mouse heart tissue macrophages and RAW264.7 cells in vitro and reduced the levels of the inflammatory cytokines IL-1β, IL-6, and TNF-α. In addition, CVB3 infection promoted the expression of TLR4, MyD88, and p-IκB-α in mouse heart tissues and RAW264.7 cells and the nuclear transfer of NF-κB p65 and inhibited the expression of IκB-α. Mechanistic studies revealed that CVB3 increased ANXA3 expression by activating the TLR4/MyD88 pathway, thereby promoting NF-κB p65 nuclear translocation and the subsequent M1 polarization of macrophages, eventually leading to the development of CVB3-induced myocarditis. CONCLUSION: Our study elucidated the role of ANXA3 in promoting CVB3-induced myocarditis, providing a potential intervention target for the treatment of VMC.
"Double-duty" dendritic cells in Xenopus laevis: Early vertebrate splenic APCs resemble conventional dendritic cells and limit native antigen presentation to B cells during a humoral response.
Flowers EM, Peng X, Cruz EJ … +1 more , Flajnik MF
Mol Immunol · 2026 Jan · PMID 41337938 · Full text
XL cells are class II, Ig-bearing cells found in splenic B cell follicles of the amphibian Xenopus laevis, bearing native antigen after immunization. XL cells are proposed to be myeloid cells serving the functions of bot...
XL cells are class II, Ig-bearing cells found in splenic B cell follicles of the amphibian Xenopus laevis, bearing native antigen after immunization. XL cells are proposed to be myeloid cells serving the functions of both classical dendritic cells (cDC) and mammalian follicular dendritic cells (FDC). Here, we compare the function and gene expression of XL cells with peritoneal macrophages (pMac), which are also class II/Ig-bearing cells. While pMacs were esterase-positive, adherent to plastic, and highly phagocytic, XL cells, like mammalian DC, adhered weakly to plastic, were esterase-low-to-negative, and were weakly phagocytic. Splenic red pulp macrophages, like pMacs, were esterase-positive. Both pMacs and XL cells bound to complement activated on zymosan particles. RNAseq was also done with IgY FACS-purified pMacs and XL cells. The pMac transcriptome was consistent with the classical macrophage lineage with high Mafb, myeloperoxidase, and CEBPA. In contrast, XL cells expressed cDC markers, chemokines CXCL13 and CCL19/CCL21, and the FDC marker VCAM1, consistent with their presumed function of attracting lymphocytes and presenting antigen. Mammalian FDC can present native antigen up to one year within B cell follicles, while ectotherms lack FDC but have myeloid cells that trap native antigen for unknown lengths of time. As shown previously, XL cells bear fluorescent antigen on their surface 16 days after immunization. However, we now show that antigen disappears by D30. Our data suggest that the myeloid XL cells indeed act as APC during a humoral immune response, but do not serve as an antigen depot to sustain memory B cells.
Verticinone inhibits cell growth and induces pyroptosis via regulating AKT pathway in papillary thyroid cancer.
Liu X, Liu Y
Mol Immunol · 2026 Jan · PMID 41330019 · Publisher ↗
BACKGROUND: Verticinone, an alkaloid isolated from Fritillaria, exhibits a range of biological activities. This study aims to investigate the effects of verticinone on papillary thyroid carcinoma (PTC), the most prevalen...
BACKGROUND: Verticinone, an alkaloid isolated from Fritillaria, exhibits a range of biological activities. This study aims to investigate the effects of verticinone on papillary thyroid carcinoma (PTC), the most prevalent histological type of thyroid cancer, as well as the potential mechanisms underlying these effects. METHODS: Cell counting kit-8, colony formation assay, and 5-ethynyl-2'-deoxyuridine staining were employed to evaluate the impact of verticinone on the proliferation capacity of PTC cells. Wound healing and Transwell assays were conducted to assess the effects of verticinone on the migration and invasion abilities of PTC cells. Flow cytometry was utilized to detect apoptosis in PTC cells. Western blot analysis was performed to measure the expression levels of relevant proteins. Additionally, network pharmacology analysis was conducted to identify potential targets of verticinone and thyroid carcinoma, and molecular docking was used to elucidate the targeting relationship. Finally, the effect of verticinone on tumor growth was evaluated using a xenograft tumor model. RESULTS: Verticinone inhibited the proliferation, migration, and invasion, and induced apoptosis and pyroptosis of PTC cells in a dose-dependent manner. Mechanically, verticinone targeted and inhibited protein kinase B (AKT), facilitating its degradation. AKT overexpression significantly eliminated the effect of verticinone on biological behavior of PTC cells. The results of xenograft tumor experiments demonstrated the inhibitory effect of verticinone on PTC tumor growth. CONCLUSION: Verticinone inhibited the growth of PTC cells and induced pyroptosis by regulating the AKT pathway.
CD38 knockout attenuates type 2 diabetic renal injury by downregulating p53 and Bax via the ERK/JNK signaling pathway.
Li D, Du Y, Zhang H … +6 more , Fang H, You J, Fan Q, Chen Y, Fang Z, Li R
Mol Immunol · 2026 Jan · PMID 41330018 · Publisher ↗
BACKGROUND: Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD), imposes substantial burdens on patients' health and socioeconomic status. Although current therapies targeting blood pressure, g...
BACKGROUND: Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD), imposes substantial burdens on patients' health and socioeconomic status. Although current therapies targeting blood pressure, glycemic control, and the renin-angiotensin system provide partial relief for DN, their efficacy remains limited. CD38, a 46-kilodalton type II transmembrane glycoprotein, is reported involved in the development of diabetes mellitus. However, the specific role and molecular mechanisms of CD38 in DN pathogenesis require further elucidation. This study aims to investigate these mechanisms. METHODS: Analyze the expression of CD38 in DN through the GEO database.Type 2 diabetic mouse models were established by using high-fat diet and streptozocin (STZ) injection. Four groups of mice were used in this experiment: WT group, DM group, CD38 group and CD38+DM group. Body weight and fasting blood glucose were monitored longitudinally. After Post-euthanasia, kidney weight and body weight were weighed, then calculated kidney weight/body weight ratio. Renal tissues underwent histopathological evaluation (H&E, PAS, PAM staining) and molecular analyses (immunohistochemistry, RT-qPCR, Western blot). RESULTS: CD38 expression was significantly higher (P < 0.05) in DN than in normal humans. And CD38 deletion ameliorated renal histopathological injury in type 2 diabetic mice in H&E staining, glycogen staining, PAM staining. RT-qPCR and Western blot results showed expressions of p53 and Bax in kidney tissues of CD38+DM group mice was significantly decreased (P < 0.05) and Bcl-2 was significantly increased (P < 0.01) compared with that of the DM group mice. Bax expression was decreased and Bcl-2 expression was increased in the renal tissues of mice of CD38+DM group when compared with mice in the DM group in immunohistochemical staining. CD38 deletion could alleviate ERK, JNK and p38 of MAPK signaling pathway(P < 0.05). Inhibition of ERK and JNK in high glucose condition ameliorated apoptosis by down-regulating p53 and Bax (P < 0.05). CONCLUSION: CD38 deletion regulated body weight and fasting blood glucose, improved renal histopathological injury and apoptosis by inhibiting MAPK signaling pathway; CD38 deficiency alleviates diabetic nephropathy by inhibiting MAPK/p53-mediated apoptosis, highlighting its role as a potential therapeutic target. CLINICAL TRIAL NUMBER: Not applicable, and this study does not yet involve clinical data.
Innovations, challenges, and gaps in the development of an effective vaccine against Neisseria gonorrhoeae, a narrative review.
Noori Goodarzi N, Pourmand MR
Mol Immunol · 2026 Jan · PMID 41330017 · Publisher ↗
Neisseria gonorrhoeae, the causative agent of gonorrhea, accounts for over 87 million new cases annually. It poses a serious threat to global health due to its high antimicrobial resistance. The development of an effecti...
Neisseria gonorrhoeae, the causative agent of gonorrhea, accounts for over 87 million new cases annually. It poses a serious threat to global health due to its high antimicrobial resistance. The development of an effective gonorrhea vaccine has been severely hampered by unique characteristics of this pathogen, particularly antigenic and phase variation of surface antigens. Additionally, the difficulty of eliciting effective mucosal immune responses and the inability of natural infection to produce long-lasting immunity further complicate vaccine development. In this review, the main obstacles to gonococcal vaccine development are discussed. Clinical trials evaluating the cross-protective effects (approximately 31-46 %) of 4CMenB vaccine against N. gonorrhoeae have been explored, along with recent advances such as recombinant proteins, multivalent and epitope-based approaches, and emerging mRNA platforms. Promising findings from preclinical studies are highlighted, together with growing role of artificial intelligence and machine learning in antigen discovery and vaccine optimization. Despite these innovations, translating theoretical approaches into safe, immunogenic, and broadly protective vaccines remains a major challenge. This review underscores the urgent need for continued interdisciplinary research to close existing gaps and develop a feasible efficient vaccine to combat drug-resistant gonorrhea.
Catalpol enhances mTORC1/HIF-1α/PDHK1-mediated oxidative metabolism that leads to promote the differentiation of Treg cells in RA.
Zhang Q, Wang F, Ding P … +4 more , Ge Y, Bao Y, Jiang B, Zhou L
Mol Immunol · 2026 Jan · PMID 41317620 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which regulatory T (Treg) cell dysfunction contributes to its pathogenesis, although the mechanisms regulating Treg differentiation remain unclear. In this stu...
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which regulatory T (Treg) cell dysfunction contributes to its pathogenesis, although the mechanisms regulating Treg differentiation remain unclear. In this study, the effects of Catalpol (CAT) on Treg differentiation and its underlying mechanisms were investigated using a CIA mouse model, with animals randomly allocated to CIA, CIA+CAT, and No CIA groups. Synovial pathology was assessed by HE staining, while naive CD4 T cells were differentiated into Tregs in vitro, and treated with CAT. Molecular docking predicted CAT-target interactions, and the mTORC1 activator NV5138 was used alongside CAT for intervention. Treg proportions and mitochondrial membrane potential were analyzed by flow cytometry, IL-10 levels were measured by ELISA, NAD/NADH was detected by assay kit, and mRNA expression of FOXP3, mTOR, Raptor, HIF-1α, and PDHK1 were determined by RT-qPCR, while protein expression was assessed by Western blotting. The results demonstrated that CAT alleviated joint symptoms in CIA mice, promoted Treg differentiation both in vivo and in vitro, and increased mitochondrial membrane potential, NAD/NADH and acetyl-CoA levels in Tregs. CAT also downregulated HIF-1α and PDHK1 mRNA and inhibited p-P70S6K/P70S6K, p-4EBP1/4EBP1, HIF-1α, and PDHK1 protein expression. Treatment with NV5138 was observed to reduce Treg differentiation and oxidative metabolism, effects which were reversed by CAT. These findings demonstrate that CAT promotes Treg differentiation and exerts anti-RA effects through inhibition of the mTORC1/HIF-1α/PDHK1 signaling pathway and enhancement of pyruvate aerobic oxidation.
Complement factor D is a drug target for metabolic-associated fatty liver disease.
Guo R, Li Z, Wu J … +10 more , Zhang Z, Shu J, Zhou X, Zhou W, Chen Y, Guan D, Wang Q, Shi Q, Yang H, Li G
Mol Immunol · 2025 Dec · PMID 41308544 · Publisher ↗
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Compl...
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Complement factor D (CFD), a rate-limiting serine protease in the alternative complement pathway, has been suggested to be associated with metabolic diseases in previous studies. Its inhibitor, danicopan, is primarily used for paroxysmal nocturnal hemoglobinuria (PNH), but its role in metabolic liver diseases remains underexplored. Here, we assessed the role of CFD in MAFLD and danicopan therapy using HFD mice, patient sera, and hepatocytes via CRISPR knockout and pharmacological interventions. Key findings demonstrated significant upregulation of CFD in MAFLD mice livers and patient sera. Genetic CFD ablation attenuated hepatocyte lipid deposition. Danicopan reduced intracellular triglycerides/cholesterol, improved glucose tolerance, lowered ALT, and alleviated hepatic steatosis in obese mice without weight change. Mechanistically, danicopan suppressed NF-κB signaling, inhibiting lipid-related genes (CD36/FASN/ FATP2) and inflammatory mediators (MMP12/IL-6/TNF-α). These results establish CFD as a novel MAFLD mediator, validating FDA-approved danicopan's therapeutic efficacy and translational potential. This work provides critical evidence for targeting the CFD pathway in MAFLD management.
Human cord blood mononuclear cells alleviate intestinal inflammation and barrier dysfunction by regulating gut metabolites and Th17/Treg balance.
Lyu L, Ma Y, Sun X … +7 more , Luo M, Wang Z, Fang L, Li W, Chen Y, Liu S, Jia X
Mol Immunol · 2025 Dec · PMID 41297113 · Publisher ↗
BACKGROUND: Cord blood mononuclear cells (CB-MNCs) are a potential alternative therapy for inflammatory bowel disease (IBD). Gut metabolites, T helper 17 (Th17) and regulatory T (Treg) cells are crucial for intestinal he...
BACKGROUND: Cord blood mononuclear cells (CB-MNCs) are a potential alternative therapy for inflammatory bowel disease (IBD). Gut metabolites, T helper 17 (Th17) and regulatory T (Treg) cells are crucial for intestinal hemeostasis and recovery. However, the role of CB-MNCs in modulating IBD, gut metabolites and the Th17/Treg balance remains unclear. METHODS: In this study, dextran sodium sulfate (DSS) was used to induce acute colitis in male C57BL/6 J mice, followed by treatment with CB-MNCs, umbilical cord-derived mesenchymal stem cells (UC-MSCs), or mesalazine. The severity of colitis was assessed daily using the disease activity index (DAI), and feces were collected for metabolomic analysis. Upon sacrifice, the colons, mesenteric lymph nodes (MLNs) and spleens of the mice were preserved for further study. RESULTS: Our findings demonstrated that compared with UC-MSCs and mesalazine, CB-MNCs treatment had superior efficacy in improving clinical symptoms, tissue repair, promoting intestinal regeneration and integrity. While CB-MNCs were equivalent to UC-MSCs and mesalazine in terms of preserving colon length and anti-inflammatory activity. At the molecular level, CB-MNCs exhibited unique and powerful effects. CB-MNCs were found to significantly increase the abundance of cortisol, corticosterone, and several metabolites with anti-inflammatory and antioxidant activities in the feces of colitis mice. CB-MNCs were also more effective than UC-MSCs and mesalazine at maintaining Th17/Treg balance than UC-MSC and mesalazine in colitis mice. CONCLUSIONS: The intravenous injection of CB-MNCs can alleviate intestinal inflammation and barrier dysfunction by modulating gut metabolites and the Th17/Treg balance. Therefore, CB-MNCs be a promising treatment for IBD.
Novel single-chain antibody recognises complex glycan/alpha helix epitope in glycated haemoglobin using a subset of its complementarity determining regions.
Gaetani L, Jenner M, Schouten JA … +3 more , Davis P, Napier R, Dixon AM
Mol Immunol · 2025 Dec · PMID 41275817 · Publisher ↗
Understanding the molecular interactions that govern antibody recognition of glycated epitopes is crucial for developing advanced diagnostics and therapeutics. This requires identification of the region of the antigen th...
Understanding the molecular interactions that govern antibody recognition of glycated epitopes is crucial for developing advanced diagnostics and therapeutics. This requires identification of the region of the antigen that is recognized (the epitope) and the regions of the antibody that bind the antigen (the paratope). Recently, we developed a single-chain variable fragment antibody (scFv) with high affinity and specificity for a complex, non-A1c epitope of haemoglobin that is both glycated and conformational. Here, we have used immunochemical and biophysical methods, including carbene footprinting mass spectrometry, to map the scFv's epitope in human glycated haemoglobin. The epitope is composed of a glycation site at Lys-66 on the β globin chain and two α-helical regions spanning residues 9-17 and 67-72 that form a contiguous binding site on the protein's surface. The identity of the paratope within the scFv was also determined, and we found that only a subset of the predicted complementarity determining regions (CDRs) participate in interactions with the antigen. A computational model of the scFv-HbA1c complex was created and used to indicate key residues in the CDRs and framework regions that mediate paratope-epitope interaction. This work advances our understanding of the molecular basis for high-affinity binding antibodies to complex glycated epitopes and provides a foundation upon which to develop innovative diagnostics that can detect multiple glycated species in parallel.
Hdh-GSK in Pacific abalone: Insights into its roles in metamorphosis, stress response, and innate immunity.
Hanif MA, Cho DH, Kim SC … +3 more , Do Han J, Lee WK, Kho KH
Mol Immunol · 2025 Dec · PMID 41275816 · Publisher ↗
Glycogen synthase kinases (GSKs) regulate key physiological processes in eukaryotes, but their role in Pacific abalone remains unexplored. In this study, the GSK gene was identified and characterized from Pacific abalone...
Glycogen synthase kinases (GSKs) regulate key physiological processes in eukaryotes, but their role in Pacific abalone remains unexplored. In this study, the GSK gene was identified and characterized from Pacific abalone (Haliotis discus hannai), and the expression was analyzed to investigate the role of GSK in early development, stress response, and innate immunity. The Hdh-GSK cDNA sequence comprised 1436 bp, with a 456 bp open reading frame (ORF) that encodes 151 deduced amino acid residues. Structurally, the Hdh-GSK protein contains a binding site for the Batabulin ligand (an anti-tumor agent). Hdh-GSK was significantly expressed in the digestive gland, a prime immune organ in aquatic organisms. Notably, higher expression during embryonic and larval development suggests the Hdh-GSK performs a dynamic role in the early development of Pacific abalone. Furthermore, Hdh-GSK expression was significantly higher in individuals exhibiting average and rapid growth than those with stunted or minimal growth. Further, Hdh-GSK expression was upregulated during starvation. Short-term heat stress (6-12 h) upregulated its expression, while prolonged stress led to downregulation, likely linked to ROS production. Cd-toxicity downregulated Hdh-GSK expression in a dose- and time-dependent manner. Immune challenges with Vibrio parahaemolyticus, LPS and poly(I:C) significantly downregulated Hdh-GSK expression (aside from an initial slight increase with bacteria and LPS), suggesting its role in anti-inflammatory responses. Overall, this study's findings suggest that Hdh-GSK may be a key candidate gene for elucidating molecular processes during early development, growth, and innate immunity in Pacific abalone.
Association of YY1 with STING activation and the inflammatory response during early muscle injury repair.
Yan X, Hou Z, Li W … +7 more , Miao S, Zhang Z, Luo J, Tao Y, Li Q, Zhao J, Xu Z
Mol Immunol · 2025 Dec · PMID 41274107 · Publisher ↗
BACKGROUND: Skeletal muscle injury is a common sports injury. Although the cGAS-STING signaling pathway is implicated in myoblast differentiation and muscle regeneration, its precise mechanisms remain unclear. Yin Yang 1...
BACKGROUND: Skeletal muscle injury is a common sports injury. Although the cGAS-STING signaling pathway is implicated in myoblast differentiation and muscle regeneration, its precise mechanisms remain unclear. Yin Yang 1 (YY1), a multifunctional transcriptional and chromatin regulator involved in various pathologies, also requires investigation for its specific role in regeneration. OBJECTIVES: This study aimed to investigate the association between YY1 and cGAS-STING pathway activation during early muscle regeneration, and explore its potential role in the inflammatory phase of myoblast differentiation. METHODS: A skeletal muscle injury model was established in C57BL/6 mice using 1.2 % barium chloride. H&E staining evaluated muscle regeneration. Immunohistochemistry (IHC) quantified MyoG, YY1, H2Bub, and RNF20 expression. Immunofluorescence (IF) determined STING and YY1 expression. Western blotting measured cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20 protein levels. qPCR analyzed mRNA of inflammatory factors (IL-6, IL-17, IL-1β, TNF-α), myogenic regulators (MyoD, MyoG, Myf5), and signaling molecules (cGAS, STING, YY1, IRF3, caspase-3). Co-immunoprecipitation (Co-IP) assessed STING-YY1 interaction. RESULTS: Post-injury histology revealed significant pathology and inflammation. qPCR indicated upregulated mRNA levels of inflammatory factors and myogenic/signaling molecules at day 3, with partial recovery by day 7. Consistently, IHC (YY1, H2Bub, RNF20), IF (STING, YY1), and WB (cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20) all demonstrated elevated expression at day 3, declining by day 7. Co-IP confirmed a direct STING-YY1 interaction. CONCLUSION: Our findings reveal a significant association between YY1 and cGAS-STING signaling activation, suggesting that this interplay contributes to the modulation of the inflammatory response during the early phase of skeletal muscle repair.
NSUN2-mediated m⁵C methylation of HSPB1 mRNA suppresses inflammation and ferroptosis in ischemic stroke via activating the NRF2/HO-1/NQO-1 pathway.
Gao G, Zhang B, Liu N … +3 more , Liu N, Zhang Y, Du H
Mol Immunol · 2025 Dec · PMID 41274106 · Publisher ↗
Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic...
Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic mark involved in various pathological processes, yet its role in IS remains unclear. This study aimed to investigate the role of m5C modification in IS and its underlying mechanisms. In vitro, human brain microvascular endothelial cells (HBMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), while in vivo, a transient middle cerebral artery occlusion (tMCAO) mouse model was established. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of NSUN2 and heat shock protein family B member 1 (HSPB1). The contents of pro-inflammatory cytokines and ferroptosis-related indicators were measured using enzyme-linked immunosorbent assay and commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1)/NAD(P)H quinone dehydrogenase 1 (NQO-1) pathway proteins was detected by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were performed to assess the interaction between NSUN2 and HSPB1. Results showed that NSUN2 was downregulated in OGD/R-treated HBMECs and tMCAO mice. Furthermore, NSUN2 overexpression mitigated OGD/R-induced inflammation and ferroptosis. Mechanistically, NSUN2 mediated m5C methylation at site 621 in HSPB1 mRNA, enhancing its stability. Knockdown of HSPB1 abolished the protective effects of NSUN2, exacerbating inflammation and ferroptosis in OGD/R-treated HBMECs. Further investigations revealed that the NSUN2/HSPB1 axis exerted its protective role by activating the NRF2/HO-1/NQO-1 pathway. Inhibition of this pathway reversed the beneficial effects of HSPB1 overexpression. In tMCAO mice, NSUN2 overexpression reduced cerebral infarct volume, improved antioxidant capacity, and activated the NRF2/HO-1/NQO-1 pathway. In conclusion, NSUN2-mediated m⁵C methylation stabilized HSPB1 and activated the NRF2/HO-1/NQO-1 pathway, thereby mitigating inflammation and ferroptosis in IS. Targeting the NSUN2/HSPB1 axis may represent a novel therapeutic strategy for IS.
Astragalus polysaccharide promotes CD8 + T cell activity by downregulating Tim-3 to potentiate antitumor immunity.
Liu P, Wang S, Bin Y … +7 more , Xin Z, Yang H, Zhang T, Xie W, Wang K, Yin W, Zhang H
Mol Immunol · 2025 Dec · PMID 41270296 · Publisher ↗
It is well known that Astragalus polysaccharide (APS) exerts potent antitumor effects by enhancing T cell cytotoxicity via the PD-1/PD-L1 axis. However, whether APS can also modulate T cell activity via alternative check...
It is well known that Astragalus polysaccharide (APS) exerts potent antitumor effects by enhancing T cell cytotoxicity via the PD-1/PD-L1 axis. However, whether APS can also modulate T cell activity via alternative checkpoint molecules remains unclear. Here, we addressed this question using complementary in vitro and in vivo approaches. In vitro, APS reduced the Tim-3 + cell population among human PBMCs. Further analysis revealed that APS specifically affected only the proportion of Tim-3 +CD8 + T cells. Along with the decreased proportion of Tim-3 + cells, CD8 + T cell immune activity was enhanced, as shown by increased expression of the early activation molecule CD69, increased secretion of GZMB, and enhanced capacity to kill human lung cancer cells. The results of transcriptome sequencing suggested that the APS-induced downregulation of Tim-3 might be related to the regulation of the transcription factor RORB. Experiments in an in vivo B16-F10 melanoma model revealed that APS enhanced T cell function by reducing the number of tumor-infiltrating Tim-3 + T cells, consequently suppressing tumor cell proliferation in mice. Collectively, our findings demonstrate that APS reduces the Tim-3 +CD8 + T cell population among PBMCs and enhances T cell cytotoxicity, providing a novel theoretical foundation for explaining the mechanism underlying APS immunomodulation.
Investigating the role of nuclear factor erythroid 2-related factor 2 pathway on T cell & endothelial cell-based in vitro autoimmune disease model.
Özeken Hİ, Sağraç D, Kırbaş OK … +2 more , Taşlı PN, Şahin F
Mol Immunol · 2025 Dec · PMID 41240478 · Publisher ↗
Autoimmune disease is a complex condition where the immune system mistakenly attacks healthy tissues and affects millions around the world. Although there is no definitive cure or effective treatment, targeting the inter...
Autoimmune disease is a complex condition where the immune system mistakenly attacks healthy tissues and affects millions around the world. Although there is no definitive cure or effective treatment, targeting the interaction between leukocytes and vascular endothelium presents a promising strategy for reducing excessive immune infiltration. Among strategies, combating oxidative stress and inflammation by activating antioxidant and anti-inflammatory genes is the best solution to decrease immune filtration. Nuclear-factor-erythroid 2-related factor-2 (NRF2) is a key player regulating oxidative stress and inflammation. This study investigates the anti-inflammatory impacts of the NRF2 pathway on the activated T cells that nonspecifically induce endothelial inflammation. To explore this, the NRF2 pathway in Human Umbilical Vein Endothelial Cells (HUVEC) was induced by using two approaches: NRF2 gene overexpression through the lentiviral systems (NRF2OE) and synthetic inducer, tert-butyl hydroquinone (TBHQ). These types of conditioned cells were co-cultured with activated Jurkat T cells to evaluate any regulatory effects of the NRF2 protein. Here, we observed that NRF2OE HUVEC cells induced a possible phenotypic shift from pro-inflammatory Th1 cells to anti-inflammatory Treg cells through upregulation of IL10 expression and downregulation of IL2 and IL2RA. This shift may demonstrate that NRF2 and its downstream pathway may help regulate immune responses by enhancing immune tolerance and reducing inflammation. Overall, these findings highlight the NRF2 pathway as a powerful modulator of endothelial inflammation and indicate its potential as a valuable therapeutic target for treating autoimmune diseases.
Differential impact of porcine reproductive and respiratory virus and swine Influenza A virus infections on respiratory Lymph Nodes B cells and macrophages.
Hervet C, Perrin A, Renson P … +8 more , Deblanc C, Muñoz M, Meurens F, Argilaguet J, Simon G, Bourry O, Maisonnasse P, Bertho N
Mol Immunol · 2025 Dec · PMID 41218477 · Publisher ↗
Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) has a profound impact on the swine industry due to its ability to persist in infected animals. The PRRSV family exhibits considerable genetic variability, with...
Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) has a profound impact on the swine industry due to its ability to persist in infected animals. The PRRSV family exhibits considerable genetic variability, with PRRSV-1 and PRRSV-2 now classified as two distinct species (Betaarterivirus suid 1 and 2). Interestingly, both species - and their corresponding attenuated vaccine strains - can persist for months, in part by delaying the appearance of neutralizing antibodies. Leveraging recently developed tools for in-depth analysis of the previously poorly characterized porcine inverted lymph node (LN), we investigated early events in LN B cell maturation during PRRSV-1 infection and compared them to those induced by acute swine influenza A virus infection. We highlighted PRRSV-specific mechanisms, including PD-L1 upregulation in efferent macrophages, the presence of extrafollicular centrocytes, and the influx of inflammatory monocytes/macrophages. These findings are consistent with previous observations in PRRSV-2 infections and may therefore reflect conserved immune evasion mechanisms across PRRSV strains.
Therapeutic potential of AAV8-mediated IL-17RA extracellular domain gene delivery in an imiquimod-induced mouse model of psoriasis.
Xie H, Li D, Cao Y … +3 more , Lv Y, Cao C, Wu H
Mol Immunol · 2025 Dec · PMID 41218476 · Publisher ↗
OBJECTIVE: To investigate the therapeutic effects of adeno-associated virus serotype 8 (AAV8)-mediated delivery of the extracellular domain of IL-17RA (IL-17RA(ECD)) on imiquimod (IMQ)-induced psoriasiform dermatitis in...
OBJECTIVE: To investigate the therapeutic effects of adeno-associated virus serotype 8 (AAV8)-mediated delivery of the extracellular domain of IL-17RA (IL-17RA(ECD)) on imiquimod (IMQ)-induced psoriasiform dermatitis in mice. METHODS: A recombinant AAV core plasmid encoding murine IL-17RA-ECD (pAAV-mIL17RA(ECD)) was generated by gene synthesis and validated for secretory expression in HEK293T cells. The recombinant AAV8 vector carrying mIL-17RA(ECD) was produced by co-transfection of pAAV-mIL17RA(ECD), helper plasmid, and AAV8 capsid plasmid. In vivo, mice were divided into four groups (Vaseline, IMQ, Luciferase+IMQ, and IL-17RA+IMQ; n = 5 per group). On day 1, mice in the treatment group received subcutaneous injections of AAV8 vector encoding luciferase or mIL-17RA(ECD). Disease progression was monitored through body weight, photography, and PASI scoring. Histopathological changes were assessed by H&E staining, and potential viral toxicity was examined in heart, liver, lung, and kidney tissues. Expression of inflammatory cytokines (TNF-α, IL-6, IL-1β，Defb4) at both mRNA and protein levels was measured by qPCR and ELISA. RESULTS: The recombinant plasmid pAAV-mIL17RA(ECD) was successfully constructed and demonstrated efficient secretory expression. AAV8-mediated mIL-17RA(ECD) expression significantly alleviated IMQ-induced psoriasiform dermatitis (P < 0.05) and markedly suppressed the upregulation of inflammatory cytokines in skin and serum at both transcriptional and protein levels (P < 0.05). CONCLUSION: AAV8-mediated IL-17RA(ECD) gene delivery effectively blocks cutaneous inflammation and attenuates inflammatory cytokines overexpression in an IMQ-induced mouse model of psoriasis, highlighting its therapeutic potential for chronic inflammatory skin diseases.
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