Molecular Immunology[JOURNAL]
Sun
200 papers
HSP47 inhibitor Col003 attenuates thromboinflammation after cerebral ischemia-reperfusion by suppressing GPVI-mediated CD84 shedding in platelets.
Liang T, Huang H, Xie X … +10 more , Deng M, Li H, Zhou K, Xie Y, Xie Z, Li R, Long R, Yang J, Li J, Liu J
Mol Immunol · 2026 Jul · PMID 42172863 · Publisher ↗
BACKGROUND: Thromboinflammation is a major factor exacerbating neurological damage after reperfusion in ischemic stroke, with platelet collagen receptor glycoprotein VI (GPVI) activation-induced CD84 shedding and its med...
BACKGROUND: Thromboinflammation is a major factor exacerbating neurological damage after reperfusion in ischemic stroke, with platelet collagen receptor glycoprotein VI (GPVI) activation-induced CD84 shedding and its mediated CD4 + T cell migration playing a key role. Our previous work demonstrated that the HSP47 inhibitor Col003 suppresses platelet activation by inhibiting GPVI signalling, thereby downregulating platelet-derived reactive oxygen species (ROS) and inflammatory mediators such as P-selectin. However, its potential to modulate thromboinflammatory responses after cerebral ischemia-reperfusion by regulating CD84 shedding downstream of GPVI remains unclear. This study aims to investigate how Col003 mitigates thromboinflammatory responses after cerebral ischemia-reperfusion, potentially offering a novel therapeutic strategy for ischemic stroke. METHOD: The middle cerebral artery occlusion (MCAO) model was employed to simulate ischemic stroke in rats. Reperfusion was performed 2 h after ischemia onset. Col003 was administered via tail vein immediately upon reperfusion. A solvent control group received an equivalent volume of DMSO (0.4% final concentration), and a sham-operated group was also established. Cerebral infarction volume was assessed via TTC staining, and neurological deficit severity was evaluated using the Bederson neurological function score. Histopathological changes, cerebral microthrombosis, and neuronal injury were observed through HE staining and Nissl staining. Immunofluorescence staining detected platelet (CD42) and leukocyte (CD45) adhesion in microvessels (CD31) and CD4 + T cell infiltration on the infarct side. Western blot assessed inflammatory factor expression (TNF-α, IL-1β) in the infarct zone and peripheral blood platelet CD84 levels. Enzyme-linked immunosorbent assay (ELISA) measured serum sCD84 levels. Concurrently, in vitro platelet activation was simulated using collagen (a GPVI agonist) to mimic in vivo conditions, with a GPVI inhibitor serving as a parallel control. The study observed that Col003 mitigated platelet CD84 shedding by inhibiting GPVI effects. RESULTS: Col003 treatment significantly improved neurological deficits in MCAO rats, reduced infarct volume, decreased cerebral microthrombus formation and CD4 + T cell infiltration, and downregulated TNF-α and IL-1β expression. Col003 markedly decreased serum soluble CD84 (sCD84) levels while increasing platelet CD84 expression, suggesting inhibition of CD84 shedding. In vitro experiments have demonstrated that Col003 produces functional outcomes similar to those of GPVI inhibitors ((S)-S007-1558, HY-144390), significantly reducing collagen-induced CD84 shedding from platelets. CONCLUSION: The HSP47 inhibitor Col003 suppresses GPVI-mediated shedding of CD84 from platelets, alleviates platelet-mediated inflammatory responses and cerebral microthrombus formation, and reduces the infiltration of CD4 + T cells and other immune cells in the cerebral infarct region. These results indicate that targeting HSP47 produces functional effects similar to those achieved by inhibiting the GPVI pathway, thereby providing a novel potential target and therapeutic strategy for ischemic stroke.
Luteolin inhibits IL-33/ST2L-induced M2 macrophage polarization in endometriosis.
Wang W, Chen Y, Wang W … +9 more , Jiang L, Bai D, Yang Y, Wang H, Wang M, Si H, Long J, Yuan D, Li J
Mol Immunol · 2026 Jul · PMID 42167049 · Publisher ↗
BACKGROUND: Endometriosis is a chronic inflammatory disease characterized by immune microenvironment dysregulation, with the IL-33/ST2L signaling axis playing a crucial role in macrophage polarization and disease progres...
BACKGROUND: Endometriosis is a chronic inflammatory disease characterized by immune microenvironment dysregulation, with the IL-33/ST2L signaling axis playing a crucial role in macrophage polarization and disease progression. Despite growing evidence of IL-33's involvement in endometriosis pathogenesis, the mechanisms underlying IL-33-induced macrophage polarization and the therapeutic potential of a natural immunomodulator luteolin remain incompletely understood. METHODS: We investigated the effects of luteolin on IL-33/ST2L-mediated M2 macrophage polarization using in vitro cell culture models and an in vivo mouse endometriosis model. The proliferation and migration of human endometrial stromal cells (HESCs) were assessed following macrophage co-culture experiments. The MyD88/NF-κB signaling pathway and inflammatory cytokine expression were analyzed using Western blotting, RT-PCR, and ELISA. RESULTS: IL-33 significantly promoted M2 macrophage polarization, which subsequently enhanced HESC proliferation and migration. Luteolin treatment effectively suppressed IL-33/ST2L signaling, inhibited IL-33-induced M2 macrophage polarization, and reduced HESC proliferative and migratory activities. In the mouse endometriosis model, luteolin administration decreased IL-33 secretion, prevented M2 macrophage accumulation, and downregulated the MyD88/NF-κB pathway. This resulted in significant reduction of pro-inflammatory cytokines (IL-1β, TNF-α, IL-4, and IL-13) and amelioration of the local immune microenvironment. CONCLUSIONS: Our findings demonstrate that luteolin exerts therapeutic effects in endometriosis by disrupting IL-33/ST2L-mediated M2 macrophage polarization and modulating inflammatory responses. These results suggest that luteolin is a promising natural therapeutic candidate for endometriosis treatment, offering insights into immune-targeted therapeutic strategies.
Branched-chain amino acids alleviate Parkinson's neurodegeneration via microbial propionate-dependent restoration of the PI3K/Akt/mTORC1 axis.
Mi N, Ma L, Zhao J … +6 more , Bu X, Xu J, Fu J, Zhang C, Zhang Y, Yao L
Mol Immunol · 2026 Jul · PMID 42160868 · Publisher ↗
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and systemic inflammation, with increasing evidence implicating the gut-brain axis in its pathogenesis. Altered gut micro...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and systemic inflammation, with increasing evidence implicating the gut-brain axis in its pathogenesis. Altered gut microbiota composition and reduced levels of neuroprotective microbial metabolites, such as short-chain fatty acids (SCFAs), have been reported in patients with PD. Branched-chain amino acids (BCAAs), essential nutrients influenced by microbial metabolism, may contribute to neuroimmune regulation through SCFA production, particularly propionate, and modulation of PI3K/Akt/mTORC1 signaling. In this study, we investigated whether dietary BCAA supplementation influences neurodegenerative processes in PD through gut microbiota remodeling and microbial propionate production, and examined the potential involvement of the PI3K/Akt/mTORC1 signaling pathway. We combined human clinical observations with mechanistic studies in MPTP-induced PD mouse models and MPP⁺-treated SH-SY5Y neuronal cells. Gut microbiota composition was profiled using 16S rRNA sequencing, and fecal and serum metabolites were analyzed by GC-MS. Neurobehavioral performance, dopaminergic neuron integrity, apoptosis-related markers, and PI3K/Akt/mTORC1 pathway activation were evaluated using immunohistochemistry, Western blotting, and cellular assays with or without pharmacological inhibition. PD patients exhibited gut dysbiosis, reduced BCAA levels, and depletion of SCFA-producing taxa. In mice, BCAA supplementation partially restored microbial composition and enhanced predicted propionate biosynthesis pathways. Propionate administration improved motor performance, preserved dopaminergic neurons, mitigated neuroinflammatory responses, and reduced apoptosis in vivo and in vitro. Mechanistically, propionate restored PI3K, Akt, and mTORC1 phosphorylation, upregulated Bcl-2, and suppressed cleaved caspase-3, effects that were abolished by PI3K inhibition. Collectively, these findings identify a gut microbiota-BCAA-propionate axis that may influence neurodegenerative processes through modulation of PI3K/Akt/mTORC1 signaling, highlighting microbial metabolites as potential modulators of gut-brain communication in PD.
Local immune responses in tick-bite skin during SFTSV infection are associated with type I interferon signaling and monocyte-lineage cell recruitment.
Lau ACC, Mori H, Sakai Y … +9 more , Shimoda H, Nagata N, Matsumura T, Shimojima M, Toyoda A, Hayasaka D, Suzuki T, Ebihara H, Takano A
Mol Immunol · 2026 Jul · PMID 42150352 · Publisher ↗
The skin harbors a complex immune microenvironment that integrates innate and adaptive components and plays a critical role in vector-borne pathogen transmission. To investigate immune responses during tick-mediated tran...
The skin harbors a complex immune microenvironment that integrates innate and adaptive components and plays a critical role in vector-borne pathogen transmission. To investigate immune responses during tick-mediated transmission of Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), we analyzed skin from BALB/c mice bitten by artificially infected Amblyomma testudinarium nymphs. Skin samples were collected at time points corresponding to peak viral RNA levels (days 6-7 post-attachment) and analyzed by transcriptomics, followed by real-time PCR and immunohistochemical (IHC) analyses. Transcriptomic analysis revealed increased expression of immune-related genes, particularly those associated with type I interferon signaling. Interferon-stimulated genes (e.g., Rsad2, Ifit family members) and monocyte-associated markers (e.g., Ly6c2) were elevated in RNA sequencing data, while real-time PCR analysis showed similar trends but did not reach statistical significance. IHC revealed colocalization of viral antigens with macrophages in the infected skin, as characterized by Iba1 expression. Further analysis demonstrated a higher density of Ly6c2-positive inflammatory monocytes, consistent with transcriptomic observations. In addition, BST2 (Tetherin) expression was increased, consistent with activation of a localized Type I IFN-mediated antiviral response. However, the strong inflammatory response induced by tick feeding may obscure infection-specific transcriptional changes at these later time points. Overall, our findings demonstrate that tick-mediated SFTSV infection was associated with interferon-related gene expression and recruitment of monocyte-lineage cells at the skin interface, while highlighting the complex interplay between viral infection and tick-induced host responses.
Transcriptomic sequencing analysis of the tumor microenvironment atlas and potential mechanisms of metastasis in papillary thyroid carcinoma.
An H, Zhang W, Niu H … +6 more , Liang W, Lv B, Wu S, Xu L, Li W, Gao S
Mol Immunol · 2026 Jul · PMID 42134246 · Publisher ↗
Papillary thyroid carcinoma (PTC) is the most prevalent thyroid malignancy and its incidence continues to rise. Although prognosis is generally favorable, overdiagnosis, overtreatment, and occasional lethal complications...
Papillary thyroid carcinoma (PTC) is the most prevalent thyroid malignancy and its incidence continues to rise. Although prognosis is generally favorable, overdiagnosis, overtreatment, and occasional lethal complications persist. To clarify the micro-environmental basis of PTC metastasis, we integrated single-cell RNA-seq from tumor (T), peritumoral thyroid (PT) and lymph-node (LN) tissues with bulk transcriptomes. Metastatic (M) and non-metastatic (NM) cases were compared, and machine-learning models were built to predict lymph-node status and outcome. Our atlas delineates highly heterogeneous ecosystems across T, PT and LN samples. Within T/NK lymphocytes, both immune-activating and immune-suppressive subsets coexist; NK and CD4+TNFRSF4 cells were selectively enriched in M tumors, implying heterogeneous anti-tumor responses. Among myeloid cells, a Mac-APOC1 subset displayed tumor-associated macrophage/M2 features, consistent with immune escape and dissemination. Dendritic cells differed markedly in antigen presentation and chemotaxis, while RGS5+ myCAFs, markedly expanded in M samples from T and LN, up-regulated metabolic and ribosomal pathways. Trajectory analysis uncovered dynamic CAF state transitions. Tumor epithelial cells followed multiple developmental branches, with those linked to LN invasion predicting poorer survival. A random-forest classifier achieved 0.98 accuracy for N-stage, and a lasso-Cox signature (C-index > 0.9) robustly stratified survival, underscoring the clinical relevance of the identified genes. Collectively, this work reveals the cellular and functional heterogeneity that drives PTC progression, identifies metastasis-associated subpopulations, and demonstrates the utility of machine learning for precise prediction of lymph-node metastasis and patient prognosis, offering a foundation for tailored therapeutic strategies.
CBL proto-oncogene C-mediated synaptophysin 1 regulates prostate cancer progression in the TGF-beta signalling pathway.
Tong J, Hu L, Liu Q … +1 more , Tian D
Mol Immunol · 2026 Jul · PMID 42119245 · Publisher ↗
OBJECTIVE: This study aims to screen and validate the differentially expressed gene synaptophysin 1 (SYT1), which plays a key regulatory role in prostate cancer, explore its function and potential regulatory mechanisms,...
OBJECTIVE: This study aims to screen and validate the differentially expressed gene synaptophysin 1 (SYT1), which plays a key regulatory role in prostate cancer, explore its function and potential regulatory mechanisms, and clarify its biological role and molecular mechanisms in the malignant progression of prostate cancer. METHODS: Differential expression analysis was performed using the GEO database dataset GSE69223, combined with the TIMER and UALCAN databases to validate the expression levels and prognostic value of the candidate gene SYT1. To further ensure the biological plausibility of the results, this study selected cell lines representing different prostate cancer subtypes and disease stages, including the normal epithelial cell line RWPE-1, the adenocarcinoma-like AR⁺ cell line LNCaP, the basal-like/AR⁻ cell line PC3, and the neuroendocrine cell line NCI-H660, and assessed differences in SYT1 expression using qRT-PCR and Western blot analysis. SYT1-overexpressing cell lines were established, and their effects on prostate cancer cell proliferation, migration, and invasion were assessed using EDU, colony formation, scratch, and Transwell assays. Using UbiBrowser, we predicted potential E3 ubiquitin ligases for SYT1 and screened CBL proto-oncogene C (CBLC) as a candidate upstream regulatory factor through differential analysis. We validated the regulatory role of CBLC in SYT1 ubiquitination and degradation via immunoprecipitation experiments and explored its mechanism of action through functional interaction experiments and signalling pathway analysis. RESULTS: SYT1 is significantly downregulated in prostate cancer tissues, and its downregulation is associated with poor prognosis in prostate cancer. Overexpression of SYT1 significantly inhibits the proliferation, migration, and invasion of prostate cancer cells. CBLC is highly expressed in prostate cancer and promotes the ubiquitination and degradation of SYT1. Knocking down CBLC reduces the ubiquitination level of SYT1 and stabilises its protein expression. Overexpression of CBLC partially reverses the antitumour effects mediated by SYT1. Mechanistic studies indicate that SYT1 exerts its antitumour function by inhibiting the TGF-β/SMAD signalling pathway, while CBLC interferes with this pathway by promoting its degradation. CONCLUSION: Prostate cancer may have SYT1 as a tumor suppressor gene, and the E3 ligase CBLC regulates its ubiquitin-mediated degradation. SYT1 inhibits tumour progression by suppressing the TGF-β/SMAD signalling pathway, while CBLC promotes the malignant development of prostate cancer by negatively regulating SYT1.
CSF1R signaling contributes to macrophage-associated CCL11 production and eosinophil recruitment in murine allergic conjunctivitis.
Du J, Wu J, Tan X … +8 more , Xie J, Zhuang Z, Lan H, Xue Y, Fu T, Gu J, Li Z, Liu J
Mol Immunol · 2026 Jul · PMID 42105679 · Publisher ↗
Allergic conjunctivitis (AC) is a prevalent ocular surface inflammatory disorder with limited therapeutic options. In this study, we investigated the role of colony-stimulating factor 1 receptor (CSF1R) in an ovalbumin (...
Allergic conjunctivitis (AC) is a prevalent ocular surface inflammatory disorder with limited therapeutic options. In this study, we investigated the role of colony-stimulating factor 1 receptor (CSF1R) in an ovalbumin (OVA)-induced murine model of AC. Conjunctival expression of CSF1R and its ligands, interleukin-34 (IL-34) and colony-stimulating factor 1 (CSF1), was significantly upregulated following OVA challenge. Pharmacological inhibition of CSF1R with BLZ945 alleviated clinical symptoms, reduced the infiltration of CD45⁺ leukocytes and eosinophils, and attenuated an M2-associated macrophage phenotype in the conjunctiva. Similar suppression of eosinophil infiltration was observed with a second CSF1R inhibitor, AZD7507. In addition, conjunctival CD206⁺ macrophages with an M2-associated phenotype expressed C-C motif chemokine ligand 11 (CCL11), which was elevated in AC and downregulated by CSF1R inhibition. Recombinant CCL11 significantly restored eosinophil infiltration in BLZ945-treated mice, supporting a role for CCL11 as a downstream effector of CSF1R signaling in this model. Collectively, these findings support a contributory role for CSF1R signaling in macrophage-associated eosinophilic inflammation in murine AC and suggest that targeting CSF1R may represent a potential therapeutic strategy for ocular allergic disease.
Acupuncture enhances warm kidney and spleen granules efficacy in diabetic diarrhea through synergistic p300/CBP inhibition and Nrf2/HO-1 pathway activation.
Wang Z, Li X, Tan Y … +4 more , Wang Y, Deng Y, Liu Y, Liu D
Mol Immunol · 2026 Jul · PMID 42105678 · Publisher ↗
Diabetic diarrhea (DD), affecting ∼20% of diabetic patients, lacks effective pharmacological treatment. This study investigates Warm Kidney and Spleen Granules (WKSG) combined with acupuncture for treating DD, focusing o...
Diabetic diarrhea (DD), affecting ∼20% of diabetic patients, lacks effective pharmacological treatment. This study investigates Warm Kidney and Spleen Granules (WKSG) combined with acupuncture for treating DD, focusing on p300/CBP-H3K27ac pathway and antioxidant/inflammatory signaling mechanisms. Male Wistar rats with HFD/STZ-induced DD received WKSG (1 g/day, 14 days), acupuncture (daily for 4 weeks; seven acupoints), or combined therapy over 35 days. Additional diabetic rats and high-glucose-stimulated Caco-2 cells were used for mechanistic validation of p300/CBP pathway involvement through p300 overexpression/silencing and pharmacological activation with CTPB. Clinical parameters such as body weight, fasting blood glucose, defecation frequency, and fecal moisture content were assessed weekly. Intestinal permeability was evaluated via transepithelial electrical resistance (TEER) and in vivo FITC-dextran permeability. Tight junction proteins (ZO-1/occludin), oxidative stress markers (ROS/MDA/SOD/GSH), p300/CBP-H3K27ac expression, Nrf2/HO-1 activation, NF-κB phosphorylation, and inflammatory cytokines (TNF-α/IL-6) were measured by Western blotting, qPCR, and ELISA. Mechanistic causality was established using p300 overexpression (oe-p300) and silencing (si-p300) lentiviral vectors in both animals and high-glucose-stimulated Caco-2 intestinal epithelial cells. Epithelial apoptosis was assessed by flow cytometry. STZ-treatment elevated colonic p300/CBP-H3K27ac, oxidative stress, inflammatory cytokines, and intestinal permeability while reducing body weight, tight junction proteins, and antioxidant enzymes. WKSG suppressed p300/CBP-HAT activity, reduced ROS/MDA, restored SOD/GSH, activated Nrf2/HO-1, inhibited NF-κB and TNF-α/IL-6, and restored barrier function; these effects were reversed by p300 overexpression. In Caco-2 cells, WKSG suppressed p300/CBP-mediated H3K27ac acetylation. Combined acupuncture and WKSG synergistically enhanced all parameters beyond monotherapy, reducing apoptosis rates further. Overall, WKSG ameliorates DD through p300/CBP inhibition, activating Nrf2/HO-1 antioxidant defense and suppressing NF-κB-mediated inflammation. Acupuncture synergistically amplifies efficacy, establishing mechanistic rationale for integrated therapy in DD management.
The CLEC-2-podoplanin axis inhibits dendritic cells migration and prolongs allograft survival in mice.
Wang H, Zhang H, Ye D … +6 more , Zhang L, Zhang X, Wang S, Ju W, Gao Y, Ma Y
Mol Immunol · 2026 Jul · PMID 42102414 · Publisher ↗
BACKGROUND: Dendritic cell (DC) migration-triggered T cell activation is a pivotal event in transplant rejection. Previous studies have established a critical role of the C-type lectin receptor 2（CLEC-2）and podoplanin...
BACKGROUND: Dendritic cell (DC) migration-triggered T cell activation is a pivotal event in transplant rejection. Previous studies have established a critical role of the C-type lectin receptor 2（CLEC-2）and podoplanin (PDPN) axis in regulating DC migration. We therefore hypothesized that targeting CLEC-2-PDPN axis could prolong allograft survival in mice by impairing DC migration. MATERIALS AND METHODS: Bioinformatics analysis was performed to assess differential CLEC-2 expression between allograft and isograft tissues and to identify potential associated biological processes. Bone marrow-derived dendritic cells (BMDCs) were generated from donor mice and treated with anti-CLEC-2 to inhibit CLEC-2 function. After LPS stimulation, surface expression of costimulatory molecules and MHC class II, as well as phagocytic capacity, were analyzed. Migration in response to PDPN and CCL19 gradients and the ability to stimulate T cell proliferation were evaluated using a Transwell assay. A murine skin allograft model (BALB/c to C57BL/6) was established. Then anti-PDPN was injected into recipient mice during transplantation. Graft survival was monitored, and pathological examination of grafts, flow cytometric analysis of draining lymph nodes (assessing DC migration and T cell activation/proliferation), and serum cytokine detection by ELISA were performed. RESULTS: Bioinformatics analysis revealed that CLEC-2 was significantly upregulated in the allograft group. In vitro, CLEC-2 suppression had no significant effect on the expression of costimulatory molecules or phagocytosis in dendritic cells. However, it specifically inhibited PDPN-mediated migration and suppressed T cell proliferation in the Transwell assay. Anti-PDPN treatment significantly prolonged skin allograft survival and attenuated rejection in mice. Flow cytometry revealed a reduced proportion of migratory DCs, particularly of the cDC2 subset in the draining lymph nodes of treated mice. Furthermore, both CD4 + and CD8 +T cell proliferation and activation were markedly suppressed. ELISA results showed decreased serum levels of IL-18 and IL-1β, while elevated IL-10. CONCLUSION: Targeting the CLEC-2-PDPN axis significantly prolongs murine allograft survival via the inhibiting DC migration and subsequent T-cell proliferative responses.
Edwardsiella piscicida effector VgrG contributes to NCOA4-dependent ferritinophagy as a bacterial survival strategy in fish.
Xiong D, Liu J, Wang Z … +2 more , Ma X, Zhou H
Mol Immunol · 2026 Jul · PMID 42102413 · Publisher ↗
Edwardsiella piscicida is an intracellular bacterial pathogen that causes intestinal injury and hemorrhagic sepsis in marine and freshwater animals. VgrG (valine-glycine repeat protein G) has been identified as a crucial...
Edwardsiella piscicida is an intracellular bacterial pathogen that causes intestinal injury and hemorrhagic sepsis in marine and freshwater animals. VgrG (valine-glycine repeat protein G) has been identified as a crucial virulence factor in the type VI secretion system (T6SS) of the bacterium, but its role and mechanism involved in E. piscicida-host interactions remain unclear. In this study, we found that the wild-type E. piscicida strain markedly induced host cell ferritin degradation and elevated intracellular Fe²⁺ levels, but a vgrG deletion mutant (ΔvgrG) strain failed to induce similar effects in fish cells, indicating the role of VgrG in the regulation of iron metabolism. However, in the NCOA4 (nuclear receptor coactivator 4, a selective cargo receptor that binds ferritin)-knockout fish cells, VgrG did not alter ferritin protein expression and E. piscicida-promoted intracellular Fe²⁺ levels, suggesting that VgrG caused iron storage disorders via NCOA4-dependent ferritinophagy. In support of this notion, VgrG overexpression was found to facilitate the co-localization of ferritin with autophagosomes and lysosomes, and also drove the interaction of NCOA4 with lysosomes, strengthening the involvement of this effector in mediating NCOA4-dependent ferritinophagy. Notably, in NCOA4-knockout cells, the inhibitory effect of VgrG on the intracellular growth of E. piscicida was further magnified, particularly highlighting the role of VgrG-induced ferritinophagy in augmenting bacterial intracellular survival. Moreover, zebrafish infected with the ΔvgrG strain had a much higher survival rate than those infected with the wild-type strain. In summary, our data revealed a new function of VgrG in maintaining the persistence of E. piscicida within host cells, which advanced our understanding of how intracellular pathogens target ferritinophagy to evade the host's immune surveillance. Moreover, this work also supported the potential for developing defense strategies against E. piscicida based on the VgrG-induced ferritinophagy response in fish.
PIAS1 attenuates the progression of abdominal aortic aneurysm by stabilizing PPARγ through SUMOylation.
Wang H, Dai R, Wang J … +4 more , Wu K, Yang B, Feng Y, Zhao L
Mol Immunol · 2026 Jul · PMID 42102412 · Publisher ↗
BACKGROUND AND PURPOSE: Protein inhibitor of activated STAT 1 (PIAS1) functions as a SUMO E3 ligase, regulating cardiovascular diseases by promoting the SUMOylation of target proteins; however, its role in abdominal aort...
BACKGROUND AND PURPOSE: Protein inhibitor of activated STAT 1 (PIAS1) functions as a SUMO E3 ligase, regulating cardiovascular diseases by promoting the SUMOylation of target proteins; however, its role in abdominal aortic aneurysm (AAA) remains unclear. Currently, molecular targeted therapies for AAA are still very limited. This study aimed to clarify whether PIAS1 regulates the stability of the PPARγ protein through SUMOylation to elucidate its molecular mechanisms in AAA formation and to evaluate its potential as a novel therapeutic target. METHODS: AAA rat models were established via the infusion of porcine pancreatic elastase, and an in vitro cell model was constructed by treating human umbilical vein endothelial cells (HUVECs) with Ang II. Flow cytometry, ELISA, H&E staining, and EVG staining were used to assess cell and abdominal aortic tissue damage, while RT-qPCR and Western blotting were used to detect the expression of relevant genes and proteins. RESULTS: This study revealed that PIAS1 is expressed at low levels in AAA. The overexpression of PIAS1 effectively inhibited Ang II-induced lipid accumulation and inflammatory responses in HUVECs and AAA rats, alleviated pathological damage and apoptosis in the abdominal aorta, and alleviated the progression of AAA. With respect to the regulatory mechanism, the SUMOylation and expression levels of PPARγ are downregulated in AAA. PIAS1 primarily stabilizes PPARγ expression by promoting its SUMOylation, thereby inhibiting lipid accumulation and inflammatory responses. Further studies revealed that SENP3 is highly expressed in AAA and that PIAS1 can downregulate SENP3 levels, thereby attenuating its deSUMOylation effect on PPARγ and ultimately promoting the SUMOylation and expression of PPARγ. CONCLUSION: PIAS1 alleviates the progression of AAA by inhibiting SENP3 expression, thereby promoting PPARγ SUMOylation and protein expression, which in turn reduces lipid accumulation and inflammatory responses.
Promoting keratinocyte psoriasiform changes and IL-17RE expression: Potential role of GLT1D1 in linear psoriasis.
Cheng Y, Chen L, Lin J … +4 more , Peng L, Xiong H, Liu G, Shen Z
Mol Immunol · 2026 Jul · PMID 42090972 · Publisher ↗
BACKGROUND: Linear psoriasis is a rare variant of psoriasis characterized by erythema and scaling along the Blaschko lines. Its pathogenesis remains unknown. OBJECTIVE: To investigate the molecular and immunological mech...
BACKGROUND: Linear psoriasis is a rare variant of psoriasis characterized by erythema and scaling along the Blaschko lines. Its pathogenesis remains unknown. OBJECTIVE: To investigate the molecular and immunological mechanisms of linear psoriasis through gene mutation analysis and in vitro experiments and identify potential combined therapeutic targets for psoriasis. METHODS: Whole-exome sequencing was performed on linear lesion, clinically normal skin, and peripheral blood from linear psoriasis patient to identify somatic mutations. Candidate gene expression was assessed using public RNA-seq data of linear and classic psoriasis vulgaris, dataset before and after IL-17 antagonist Brodalumab treatment, and single-cell data of recurrent psoriasis lesions. Immunofluorescence staining confirmed gene expression and distribution. In vitro keratinocyte assays evaluated effects on proliferation and inflammation. Based on these findings, the patient received IL-17 antagonist therapy (Ixekizumab). RESULTS: An increased copy number variant of Glycosyltransferase 1 Domain Containing 1 (GLT1D1), not previously reported, was identified in the epidermis of linear psoriasis. GLT1D1 was highly expressed in both linear psoriasis and classic psoriasis vulgaris, as well as in recurrent lesions and in patients who failed to achieve PASI75 with IL-17 antagonist therapy. In keratinocytes, GLT1D1 overexpression promoted cell proliferation, enhanced proinflammatory cytokine secretion, and activated IL-17 signaling, particularly via IL-17RE upregulation. In imiquimod-induced mouse models, GLT1D1 overexpression aggravated psoriasiform inflammation. Clinical improvement was observed in the patient after treatment with ixekizumab. CONCLUSION: GLT1D1, with an abnormally high copy number, may contribute to psoriasiform changes in keratinocytes by promoting proliferation, increasing proinflammatory cytokine secretion, and enhancing IL-17RE expression.
Quercetin attenuates LTA-induced tight junction disruption in mammary epithelial cells by modulating autophagy via the AMPK/mTOR pathway.
Song L, Li X, Wang L … +2 more , Liu J, Xiao L
Mol Immunol · 2026 Jul · PMID 42090971 · Publisher ↗
Mastitis in dairy cows impairs lactation and limits the development of the dairy industry. Lipoteichoic acid (LTA), a virulence factor of Staphylococcus aureus, disrupts the blood-milk barrier in the mammary gland. Querc...
Mastitis in dairy cows impairs lactation and limits the development of the dairy industry. Lipoteichoic acid (LTA), a virulence factor of Staphylococcus aureus, disrupts the blood-milk barrier in the mammary gland. Quercetin, known for its anti-inflammatory and antibacterial properties, was evaluated for its protective effects against LTA-induced tight junction (TJ) injury. We established a TJ injury model using LTA-treated MAC-T cells (a mammary epithelial cell line) and mouse mammary tissue. Results demonstrated that LTA compromised TJ integrity and induced dysregulated autophagy in MAC-T cells. Notably, quercetin treatment was associated with the inhibition of this autophagic dysregulation and attenuated the LTA-induced disruption of TJ protein expression. Further mechanistic studies revealed that both quercetin and Compound C (CC, an AMPK inhibitor) reduced autophagy levels and mitigated the LTA-induced decline in key TJ proteins, suggesting that quercetin is associated with the attenuation of LTA-induced TJ integrity disruption under inflammatory stress, which correlates with modulated changes in AMPK phosphorylation and the mTOR signaling pathway. In vivo mouse experiments confirmed that quercetin acts as a dual-action modulator that regulates baseline signaling while attenuating LTA-induced TJ protein damage. This protective process is mediated through the modulation of AMPK/mTOR-dependent autophagy, thereby suppressing LTA-induced autophagic dysregulation. These findings provide a theoretical basis for further research into alternative, non-antibiotic strategies for mastitis control.
Neutrophil extracellular traps-related biomarkers in idiopathic pulmonary arterial hypertension: A machine learning-based identification and experimental validation study.
Ma Q, You S
Mol Immunol · 2026 Jul · PMID 42085826 · Publisher ↗
Neutrophil extracellular traps (NETs) are increasingly recognized as critical mediators in vascular inflammation and remodeling, yet their molecular mechanisms in idiopathic pulmonary arterial hypertension (IPAH) pathoge...
Neutrophil extracellular traps (NETs) are increasingly recognized as critical mediators in vascular inflammation and remodeling, yet their molecular mechanisms in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis remain largely unexplored. This study employed integrated bioinformatics approaches and experimental validation to identify NETs-related biomarkers in IPAH. We performed weighted gene co-expression network analysis (WGCNA) on merged transcriptomic datasets (GSE117261 and GSE48149, comprising 40 IPAH and 34 control samples), identifying a blue module significantly correlated with IPAH status. By intersecting module genes with 69 known NETs-related genes, we obtained 19 differentially expressed NETs-related genes (DE-NRGs) enriched in neutrophil degranulation, interleukin-6 regulation, and NETs formation pathways. Three complementary machine learning algorithms converged on five key biomarkers: CSF3R, MGAM, ITGAM, TLR8 (downregulated), and SELP (upregulated). These biomarkers demonstrated strong diagnostic performance in an independent validation cohort, with an area under the curve greater than 0.8. Immune infiltration analysis revealed significantly decreased neutrophils, macrophages, and myeloid-derived suppressor cells in IPAH patients. Single-cell RNA sequencing validated cell-type-specific expression patterns, with CSF3R predominantly in neutrophils, ITGAM/TLR8 in macrophages, and SELP in endothelial cells. Critically, monocrotaline-induced rat pulmonary arterial hypertension model confirmed significant downregulation of MGAM, CSF3R and ITGAM at protein levels. Our findings establish a NETs-related molecular signature for IPAH diagnosis and reveal impaired neutrophil function as a key pathogenic mechanism in IPAH, providing novel molecular targets for therapeutic intervention and risk stratification.
Sinigrin inhibits PD-L1 expression via suppressing the JAK-STAT signaling pathway to modulate the tumor immune microenvironment in lung cancer.
Zhu N, Yu Z
Mol Immunol · 2026 Jul · PMID 42070508 · Publisher ↗
Lung cancer is one of the most common malignant tumors worldwide. During the development and progression of lung cancer, the increase in PD-L1 expression inhibits T cell activity, leading to an immunosuppressive tumor mi...
Lung cancer is one of the most common malignant tumors worldwide. During the development and progression of lung cancer, the increase in PD-L1 expression inhibits T cell activity, leading to an immunosuppressive tumor microenvironment. Sinigrin (Sin) is a natural aliphatic glucoside with various pharmacological effects such as anti-cancer and immunomodulation. However, its role in lung cancer and the underlying mechanism remain unclear. This study aims to explore the therapeutic potential and molecular mechanism of sinigrin in improving the immune microenvironment of lung cancer. Experiments conducted in vitro demonstrated that sinigrin can effectively inhibit the viability, proliferation and migration of cancer cells, promote their apoptosis, and significantly reduce the expression level of PD-L1. Moreover, the effect of sinigrin on cancer cells is dose-dependent. The results of in vivo experiments indicated that sinigrin can effectively inhibit tumor growth and proliferation, promote tumor cell apoptosis, suppress the expression of PD-L1, enhance T-cell activation, and improve the tumor immune microenvironment. Network pharmacology and in vitro experimental analyses revealed that sinigrin exerts its therapeutic effect by inhibiting the expression of PD-L1 through the JAK/STAT signaling pathway. Sinigrin inhibits the expression of PD-L1 by suppressing the JAK-STAT signaling pathway, thereby improving the immune microenvironment of lung cancer and providing an effective therapeutic strategy for blocking the progression of lung cancer.
Glutathione depletion activates cGAS-STING signaling via oxidative stress in preeclampsia.
Hu S, Liu W, Dong Y … +17 more , Wu S, Zhao S, Zheng Y, Li C, Si D, Chen J, Su S, Han J, Cao Y, Lu Y, Meng L, Xu Z, Song L, Wang Y, Lu T, Zhai Y, Cao Z
Mol Immunol · 2026 Jul · PMID 42068604 · Publisher ↗
Oxidative stress can cause double-strand breaks in DNA in patients with preeclampsia (PE), but whether the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is involved in PE remains unclear....
Oxidative stress can cause double-strand breaks in DNA in patients with preeclampsia (PE), but whether the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is involved in PE remains unclear. Here, we show that glutathione (GSH) metabolism is disrupted in placentas from PE patients, leading to increased oxidative stress and activation of the cGAS-STING pathway. Using metabolomics and and CRISPR-Cas9 generated cGAS/STING knockout human trophoblast cells, we found that GSH depletion elevate reactive oxygen species (ROS) levels in HTR-8/SVneo cells, leading to cellular DNA damage and the release of double-stranded DNA (dsDNA) into the cytosol. This activates the cGAS-STING signalling, promoting NF-κB-mediated inflammatory and type I interferon responses. This mechanism highlights the critical role of ROS-mediated DNA damage and cGAS-STING-dependent inflammation in PE development, suggesting potential therapeutic targets for its intervention.
Siglec-15 promotes M2 polarization of Kupffer cells via DAP12/IRAK-M axis to alleviate acute rejection in liver transplantation.
Luo J, Tu L, Gong J … +2 more , Mei Z, Cheng M
Mol Immunol · 2026 Jun · PMID 42066581 · Publisher ↗
BACKGROUND: Acute rejection (AR) remains a significant issue affecting the efficacy of liver transplantation, and the Kupffer cell (KC) phenotype is crucial for AR. Recent studies have indicated that Siglec-15 can regula...
BACKGROUND: Acute rejection (AR) remains a significant issue affecting the efficacy of liver transplantation, and the Kupffer cell (KC) phenotype is crucial for AR. Recent studies have indicated that Siglec-15 can regulate macrophage polarization. However, the role of Siglec-15 in liver transplantation remains unclear. METHODS: Immune tolerance (BN-BN) and immune rejection (Lewis-BN) models were developed in rats to assess the expression of Siglec-15 in KCs. Clinical specimens were also collected for further validation. Then, in vitro experiments were conducted to explore the function and specific mechanisms of Siglec-15 in regulating KC polarization. Finally, Siglec-15 was overexpressed in rats to evaluate its impact on AR. RESULTS: Compared to the immune tolerance group, the expression of Siglec-15 in KCs was lower in the immune rejection group. Similarly, Siglec-15 levels were significantly decreased in patients with AR, and Siglec-15 expression levels were significantly negatively correlated with AR severity. KCs were isolated from the liver tissue of healthy BN rats and treated with lipopolysaccharide, and overexpressing Siglec-15 promoted M2 polarization of KCs. Mechanistically, the GENEMANIA website predicted that the DNAX-activation protein 12 (DAP12)/interleukin-1 receptor-associated kinase-M (IRAK-M) pathway serves as a potential downstream target of Siglec-15. Molecular docking and in vitro experiments confirmed this result. Further silencing either DAP12 or IRAK-M via siRNA abolished the promoting effect of Siglec-15 on the M2 polarization of KCs. Furthermore, overexpressing Siglec-15 reduced AR and improved survival rates in rats. CONCLUSIONS: Siglec-15 induces M2 polarization of KCs through the DAP12/IRAK-M axis, thereby alleviating AR during liver transplantation. Siglec-15 is a potential effective target for therapeutic intervention in AR.
Puerarin and DHEA combination therapy alleviates primary dysmenorrhea via inhibition of the Hsp90ab1/p38/JNK pathway.
Zhu Z, Ruan J, Wang R … +7 more , Wang Y, Chen H, Yu X, Wen Y, Wang Y, Wang D, Tao G
Mol Immunol · 2026 Jun · PMID 42030694 · Publisher ↗
Primary dysmenorrhea (PD), a prevalent gynecological disorder, is fundamentally driven by chronic uterine inflammation, leading to severe lower abdominal pain and recurrent cramping. Given the known anti-inflammatory pro...
Primary dysmenorrhea (PD), a prevalent gynecological disorder, is fundamentally driven by chronic uterine inflammation, leading to severe lower abdominal pain and recurrent cramping. Given the known anti-inflammatory properties of Puerarin (Pue) and Dehydroepiandrosterone (DHEA), we investigated their individual and combined therapeutic effects on PD using an estradiol benzoate/oxytocin-induced mouse model. Our findings revealed that both Pue and DHEA alleviated PD symptoms, as evidenced by reduced writhing frequency, prolonged inter-writhe intervals, diminished uterine edema, lower uterine PGF2α/PGE2 ratio, decreased levels of inflammatory cytokines, and downregulated endometrial cyclooxygenase-2 (COX-2) expression. Notably, co-administration of Pue and DHEA produced superior therapeutic efficacy. Mechanistically, this combination more effectively reversed the pathological upregulation of Hsp90ab1 and the heightened phosphorylation of p38 and JNK in the PD uterus. However, lentiviral overexpression of Hsp90ab1 significantly attenuated the therapeutic benefits conferred by Pue and DHEA. Collectively, these results demonstrated that the synergistic action of Pue and DHEA represents a potent therapeutic strategy for PD, primarily through suppression of the Hsp90ab1/p38/JNK signaling and subsequent mitigation of uterine inflammation, offering a promising avenue for clinical intervention.
NAT10 promotes lung cancer progression by enhancing glutamine metabolism through increasing ac4C modification on NIT2.
Yang D, Zhu Y, Liu Y … +1 more , Dai Z
Mol Immunol · 2026 Jun · PMID 42030693 · Publisher ↗
Glutamine metabolism plays a critical role in lung cancer progression due to its substantial contribution to energy supply. NAT10 is currently the only known ac4C transferase and regulates gene expression and mRNA stabil...
Glutamine metabolism plays a critical role in lung cancer progression due to its substantial contribution to energy supply. NAT10 is currently the only known ac4C transferase and regulates gene expression and mRNA stability through ac4C modification, thereby influencing tumor progression. This study aimed to investigate the mechanisms by which NAT10 mediates glutamine metabolism in lung cancer. The UALCAN database was used to perform pan-cancer analysis and assess NAT10 expression in lung cancer. Cell viability, proliferation, and migration were evaluated to characterize malignant behaviors in lung cancer cells. Glutamine metabolism was assessed by measuring glutamine consumption, as well as α-ketoglutarate (α-KG) and ATP production. NAT10-associated genes were identified from the GSE3141 dataset and subjected to pathway enrichment analysis. The underlying mechanism was explored using methylated RNA immunoprecipitation and dual-luciferase reporter assays. The role of NAT10 in lung cancer progression in vivo was assessed using a xenograft model. Results showed that NAT10 was upregulated in lung cancer cells and promoted cell viability, proliferation, migration, and glutamine metabolism in A549 and H460 cells, whereas NAT10 inhibition reversed these effects. Mechanistically, NAT10 enhanced ac4C modification of NIT2 and increased NIT2 mRNA stability. Overexpression of NIT2 restored cell viability, proliferation, migration, and glutamine metabolism that were suppressed by NAT10 knockdown in A549 and H460 cells. Furthermore, inhibition of NAT10 reduced tumor growth and glutamine metabolism in nude mice. Collectively, our findings demonstrate that NAT10 promotes glutamine metabolism in lung cancer by enhancing ac4C modification of NIT2, providing new insights into the mechanisms underlying lung cancer progression.
Wnt7a mediates the Wnt/β-catenin signaling pathway to influence ferroptosis in T lymphocytes of HIV-infected individuals.
Tao Z, Gao J, Huang H … +9 more , Xu T, Zhang T, Liang J, Bao L, Liao S, Mo L, Chi J, Li L, Xie L
Mol Immunol · 2026 Jun · PMID 42025402 · Publisher ↗
Human Immunodeficiency Virus (HIV) infection is characterized by the depletion of human CD4 + T cells, in which ferroptosis has been identified as a contributing mechanism. Dysregulation of the canonical Wnt/β-catenin si...
Human Immunodeficiency Virus (HIV) infection is characterized by the depletion of human CD4 + T cells, in which ferroptosis has been identified as a contributing mechanism. Dysregulation of the canonical Wnt/β-catenin signaling pathway is strongly associated with HIV infection. Our findings demonstrate that Wnt7a activates this pathway. Subsequently, β-catenin translocates to the nucleus, where it interacts with the transcription factor 4 (TCF4) to regulate ferroptosis in T lymphocytes from HIV-infected individuals. Analysis of peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals revealed significantly decreased expression levels of Wnt7a, along with key Wnt/β-catenin pathway components (β-catenin, TCF4) and the ferroptosis regulator GPX4, compared to healthy controls. Concurrently, PBMCs from HIV-infected individuals exhibited elevated levels of ferroptosis. We established an in vitro HIV-infected T lymphocyte model by expanding patient-derived PBMCs using a CD3/CD28/CD2 T cell activator and IL-2. Lentiviral transduction was used to stably overexpress Wnt7a in this model. Wnt7a overexpression successfully activated the Wnt/β-catenin pathway and significantly reduced ferroptosis levels. Furthermore, pharmacological manipulation of ferroptosis modulated Wnt7a expression: treatment with the ferroptosis inhibitor Liproxstatin-1 and Ferrostatin-1 increased Wnt7a expression, while exposure to the ferroptosis inducer RSL-3 decreased it. Flow cytometry analysis confirmed that overexpressing Wnt7a significantly increased the number of CD4 + T cells compared to the control. In summary, Wnt7a activates the Wnt/β-catenin signaling pathway to reduce ferroptosis in T lymphocytes from HIV-infected individuals, likely by targeting GPX4, suggesting a potential new strategy for treating HIV infection by restoring the T lymphocyte population.
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