Pub Date : 2025-11-20DOI: 10.1016/j.molimm.2025.11.010
Peijuan Liu , Shuang Wang , Yixiao Bin , Zhiqian Xin , Haijiao Yang , Tianjiao Zhang , Wangge Xie , Ke Wang , Wen Yin , Hai Zhang
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.
{"title":"Astragalus polysaccharide promotes CD8 + T cell activity by downregulating Tim-3 to potentiate antitumor immunity","authors":"Peijuan Liu , Shuang Wang , Yixiao Bin , Zhiqian Xin , Haijiao Yang , Tianjiao Zhang , Wangge Xie , Ke Wang , Wen Yin , Hai Zhang","doi":"10.1016/j.molimm.2025.11.010","DOIUrl":"10.1016/j.molimm.2025.11.010","url":null,"abstract":"<div><div>It is well known that <em>Astragalus</em> 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.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 121-130"},"PeriodicalIF":3.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Investigating the role of nuclear factor erythroid 2–related factor 2 pathway on T cell & endothelial cell-based in vitro autoimmune disease model","authors":"Hatice İlke Özeken , Derya Sağraç , Oğuz Kaan Kırbaş , Pakize Neslihan Taşlı , Fikrettin Şahin","doi":"10.1016/j.molimm.2025.11.002","DOIUrl":"10.1016/j.molimm.2025.11.002","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 111-120"},"PeriodicalIF":3.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.molimm.2025.10.010
C. Hervet , A. Perrin , P. Renson , C. Deblanc , M. Muñoz , F. Meurens , J. Argilaguet , G. Simon , O. Bourry , P. Maisonnasse , N. Bertho
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.
{"title":"Differential impact of porcine reproductive and respiratory virus and swine Influenza A virus infections on respiratory Lymph Nodes B cells and macrophages","authors":"C. Hervet , A. Perrin , P. Renson , C. Deblanc , M. Muñoz , F. Meurens , J. Argilaguet , G. Simon , O. Bourry , P. Maisonnasse , N. Bertho","doi":"10.1016/j.molimm.2025.10.010","DOIUrl":"10.1016/j.molimm.2025.10.010","url":null,"abstract":"<div><div>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 (<em>Betaarterivirus suid</em> 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.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 98-110"},"PeriodicalIF":3.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.molimm.2025.10.013
Lu-Lu Wang , Yang Yang , Yong-Bo Feng , Han-Qing Zhao , Qian Hong , Fu-Xing Chen , Ling Chen , Lei-Qing Sun , Xiao-Ting Lü , Fei Sun , Hui Feng , Kai Chen , Zeng-Hui Liu , Li-Li Guo , Zhong-Hai Zhou
Low dose ionizing radiation exhibits immunomodulatory properties. However, the impact of various doses of ionizing radiation on the antitumor responses of γδ T cells remains uncertain. The present study aimed to investigate the effects of different doses of ionizing radiation on the proliferation, cytotoxicity and related molecular mechanisms of γδ T cells in vitro. Human γδ T cells were exposed to radiation by X-ray with different doses. CCK-8 assay was used to measure cell proliferation. Cytotoxic activity was detected using LDH release assay. Cytokines IFN-γ and TNF-α were measured by ELISA. Flow analysis was performed to determine the expressions of perforin, granzyme B and CD107a in/on γδ T cells. Protein expression of Bax, Bcl-2, p-ERK1/2, and p-p38MAPK in γδ T cells were evaluated by western blotting analysis. The results showed that γδ T cells of the 0.08 Gy dose group exhibited the most pronounced proliferation. The antitumor cytotoxicity of γδ T cells and the levels of IFN-γ and TNF-α in the 2 Gy and 4 Gy groups were higher than those in the control group. Accordingly, the expression of perforin, granzyme B, and CD107a in these two groups was upregulated significantly. Protein analysis indicated that in the 0.08 Gy group, the expression of Bcl-2 and p-ERK1/2 was significantly upregulated, whereas Bax was downregulated. In the 2.00 Gy group, the expression of p-p38MAPK was notably upregulated. These findings indicate that appropriate doses of ionizing radiation may promote γδ T cell proliferation through the ERK pathway, and enhance the cytotoxic activity of γδ T cells by upregulating critical cytokines production and the expression of cytotoxic molecules through the p38MAPK pathway.
{"title":"Appropriate doses of ionizing radiation facilitate the proliferation and anti-tumor effects of γδ T cells through ERK and p38MAPK pathways in vitro","authors":"Lu-Lu Wang , Yang Yang , Yong-Bo Feng , Han-Qing Zhao , Qian Hong , Fu-Xing Chen , Ling Chen , Lei-Qing Sun , Xiao-Ting Lü , Fei Sun , Hui Feng , Kai Chen , Zeng-Hui Liu , Li-Li Guo , Zhong-Hai Zhou","doi":"10.1016/j.molimm.2025.10.013","DOIUrl":"10.1016/j.molimm.2025.10.013","url":null,"abstract":"<div><div>Low dose ionizing radiation exhibits immunomodulatory properties. However, the impact of various doses of ionizing radiation on the antitumor responses of γδ T cells remains uncertain. The present study aimed to investigate the effects of different doses of ionizing radiation on the proliferation, cytotoxicity and related molecular mechanisms of γδ T cells <em>in vitro</em>. Human γδ T cells were exposed to radiation by X-ray with different doses. CCK-8 assay was used to measure cell proliferation. Cytotoxic activity was detected using LDH release assay. Cytokines IFN-γ and TNF-α were measured by ELISA. Flow analysis was performed to determine the expressions of perforin, granzyme B and CD107a in/on γδ T cells. Protein expression of Bax, Bcl-2, p-ERK1/2, and p-p38MAPK in γδ T cells were evaluated by western blotting analysis. The results showed that γδ T cells of the 0.08 Gy dose group exhibited the most pronounced proliferation. The antitumor cytotoxicity of γδ T cells and the levels of IFN-γ and TNF-α in the 2 Gy and 4 Gy groups were higher than those in the control group. Accordingly, the expression of perforin, granzyme B, and CD107a in these two groups was upregulated significantly. Protein analysis indicated that in the 0.08 Gy group, the expression of Bcl-2 and p-ERK1/2 was significantly upregulated, whereas Bax was downregulated. In the 2.00 Gy group, the expression of p-p38MAPK was notably upregulated. These findings indicate that appropriate doses of ionizing radiation may promote γδ T cell proliferation through the ERK pathway, and enhance the cytotoxic activity of γδ T cells by upregulating critical cytokines production and the expression of cytotoxic molecules through the p38MAPK pathway.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 80-88"},"PeriodicalIF":3.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.molimm.2025.11.001
Huibin Xie , Danping Li , Yu Cao , Yafeng Lv , Chunyu Cao , Hongyan Wu
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.
{"title":"Therapeutic potential of AAV8-mediated IL-17RA extracellular domain gene delivery in an imiquimod-induced mouse model of psoriasis.","authors":"Huibin Xie , Danping Li , Yu Cao , Yafeng Lv , Chunyu Cao , Hongyan Wu","doi":"10.1016/j.molimm.2025.11.001","DOIUrl":"10.1016/j.molimm.2025.11.001","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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).</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 89-97"},"PeriodicalIF":3.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.molimm.2025.10.015
Chenglong Sun , Yang Zhang , Jinfeng Liu , Nan Wei , Fei Li , Yuan Fang , Yijun Li , Songguo Li , Xiaokai Ma , Zhanggui Wang , Xinyu Wang
Objective
To clarify the impact of X-ray irradiation combined with PD-1 immune checkpoint inhibitor treatment on lung tissue in a mouse model of radiation-induced lung injury (RILI) and to investigate its underlying mechanisms.
Methods
A mouse RILI model was established by a single 16 Gy dose of whole-thorax irradiation. Mice were then treated with either an PD-1 inhibitor or a control. Lung injury and fibrosis were assessed by histological staining. Inflammatory cytokine levels (TNF-α, IL-6) were measured by ELISA. Macrophage M1 polarization was analyzed by flow cytometry and immunohistochemistry. The activation of the NF-κB signaling pathway was evaluated by Western blot.
Results
The lung injury indices in the group treated with irradiation combined with PD-1 inhibitor were higher than those in the irradiation-only group. Mechanistic studies found that PD-1 inhibitors promoted the activation of the NF-κB signaling pathway and simultaneously regulated macrophage polarization in lung tissue, promoting the differentiation of M1-type pro-inflammatory cells.
Conclusion
Whole-thorax X-ray irradiation combined with PD-1 inhibitors can exacerbate lung injury and pulmonary fibrosis in mice, and the mechanism of action may be through the regulation of NF-κB signaling pathway activation to promote macrophage polarization towards the M1 type.
{"title":"Molecular pathways of radiation-induced lung damage: Effects of X-ray and Anti-PD-1 combination in a murine model","authors":"Chenglong Sun , Yang Zhang , Jinfeng Liu , Nan Wei , Fei Li , Yuan Fang , Yijun Li , Songguo Li , Xiaokai Ma , Zhanggui Wang , Xinyu Wang","doi":"10.1016/j.molimm.2025.10.015","DOIUrl":"10.1016/j.molimm.2025.10.015","url":null,"abstract":"<div><h3>Objective</h3><div>To clarify the impact of X-ray irradiation combined with PD-1 immune checkpoint inhibitor treatment on lung tissue in a mouse model of radiation-induced lung injury (RILI) and to investigate its underlying mechanisms.</div></div><div><h3>Methods</h3><div>A mouse RILI model was established by a single 16 Gy dose of whole-thorax irradiation. Mice were then treated with either an PD-1 inhibitor or a control. Lung injury and fibrosis were assessed by histological staining. Inflammatory cytokine levels (TNF-α, IL-6) were measured by ELISA. Macrophage M1 polarization was analyzed by flow cytometry and immunohistochemistry. The activation of the NF-κB signaling pathway was evaluated by Western blot.</div></div><div><h3>Results</h3><div>The lung injury indices in the group treated with irradiation combined with PD-1 inhibitor were higher than those in the irradiation-only group. Mechanistic studies found that PD-1 inhibitors promoted the activation of the NF-κB signaling pathway and simultaneously regulated macrophage polarization in lung tissue, promoting the differentiation of M1-type pro-inflammatory cells.</div></div><div><h3>Conclusion</h3><div>Whole-thorax X-ray irradiation combined with PD-1 inhibitors can exacerbate lung injury and pulmonary fibrosis in mice, and the mechanism of action may be through the regulation of NF-κB signaling pathway activation to promote macrophage polarization towards the M1 type.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 73-79"},"PeriodicalIF":3.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.molimm.2025.10.014
Yan Zhang , Lei Yang , Huiting Mu , Na Li , Xuejia Wang , Hualan Lei , Mingjie Pang
The pathogenesis of viral myocarditis (VMC) is closely related to microbial infections, among which Coxsackievirus B3 (CVB3) is a common pathogenic microorganism. The aim of this study is to explore the potential mechanism of USP18 in VMC caused by CVB3 infection. In this study, mice were injected intraperitoneally with 100 μL of CVB3 (103 TCID50) to construct a VMC mouse model, and HL-1 cells were exposed to CVB3 to establish a VMC cell model. The expression of related genes and proteins was detected using RTqPCR and Western blotting, and damage to cells and myocardial tissues was evaluated using ELISA, immunofluorescence, HE staining, etc. In this study, USP18 expression was upregulated in VMC- and CVB3-infected mice and HL-1 cells. USP18 knockdown not only promoted the expression of inflammatory factors (IL-18 and IL-1β), pyroptosis-related proteins (caspase-1, NLRP3, and GSDMD) and fibrosis-related proteins (α-SMA, Collagen I, and FN1) but also promoted the expression of myocardial injury markers (LDH, CK-MB, and cTnI) in vivo, aggravating the pathological damage to myocardial tissues. Moreover, USP18 overexpression inhibited CVB3-induced pyroptosis and fibrosis. Mechanistically, USP18 stabilizes IRF7 expression through deubiquitination, thereby promoting the binding of IRF7 to NF-κB, inhibiting the nuclear translocation of NF-κB, and ultimately inhibiting CVB3-induced pyroptosis and fibrosis and improving VMC. Our study suggests that upregulating USP18 expression may represent a new target for VMC treatment.
{"title":"USP18 inhibits CVB3-induced pyroptosis and fibrosis of mouse cardiomyocytes through the IRF7/NF-κB signaling pathway","authors":"Yan Zhang , Lei Yang , Huiting Mu , Na Li , Xuejia Wang , Hualan Lei , Mingjie Pang","doi":"10.1016/j.molimm.2025.10.014","DOIUrl":"10.1016/j.molimm.2025.10.014","url":null,"abstract":"<div><div>The pathogenesis of viral myocarditis (VMC) is closely related to microbial infections, among which Coxsackievirus B3 (CVB3) is a common pathogenic microorganism. The aim of this study is to explore the potential mechanism of USP18 in VMC caused by CVB3 infection. In this study, mice were injected intraperitoneally with 100 μL of CVB3 (10<sup>3</sup> TCID50) to construct a VMC mouse model, and HL-1 cells were exposed to CVB3 to establish a VMC cell model. The expression of related genes and proteins was detected using RT<img>qPCR and Western blotting, and damage to cells and myocardial tissues was evaluated using ELISA, immunofluorescence, HE staining, etc. In this study, USP18 expression was upregulated in VMC- and CVB3-infected mice and HL-1 cells. USP18 knockdown not only promoted the expression of inflammatory factors (IL-18 and IL-1β), pyroptosis-related proteins (caspase-1, NLRP3, and GSDMD) and fibrosis-related proteins (α-SMA, Collagen I, and FN1) but also promoted the expression of myocardial injury markers (LDH, CK-MB, and cTnI) in vivo, aggravating the pathological damage to myocardial tissues. Moreover, USP18 overexpression inhibited CVB3-induced pyroptosis and fibrosis. Mechanistically, USP18 stabilizes IRF7 expression through deubiquitination, thereby promoting the binding of IRF7 to NF-κB, inhibiting the nuclear translocation of NF-κB, and ultimately inhibiting CVB3-induced pyroptosis and fibrosis and improving VMC. Our study suggests that upregulating USP18 expression may represent a new target for VMC treatment.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 62-72"},"PeriodicalIF":3.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.molimm.2025.10.009
Lizhi Cao , Xiaoying Wang , Zhongping Ning , Fandi Xie , Xiaodan Li , Yongting Chen , Qian Geng , Junchi Liu , Qian Zhu , Linlin Ma , Yanfei Li
Background
This research aimed to elucidate the roles of plasma secretory protein genes in mediating the comorbid effects between hepatocellular carcinoma (HCC) and heart failure (HF).
Methods
A comprehensive analysis utilizing Weighted Gene Co-expression Network Analysis (WGCNA), differential expression analysis, and advanced deep learning techniques was conducted to identify three plasma-secreted protein genes (Ficolin-3: FCN3, Fibroblast Activation Protein: FAP, High Mobility Group Box 2: HMGB2) as key players in the comorbid interplay between HCC and HF.
Results
Validation experiments confirmed the significant biological functions of these genes in disease pathogenesis. Additionally, dexamethasone and catechins were identified as promising candidates for pharmacological intervention in the prevention of HCC and HF.
Conclusion
These findings unveil potential mechanistic pathways of comorbidity between HCC and HF, providing novel biological markers and therapeutic targets for the prognostic evaluation and treatment of these conditions, with substantial implications for refining clinical diagnosis and therapeutic strategies.
{"title":"Plasma secretory protein genes in hepatocellular carcinoma and heart failure: Comorbidity and biological function exploration","authors":"Lizhi Cao , Xiaoying Wang , Zhongping Ning , Fandi Xie , Xiaodan Li , Yongting Chen , Qian Geng , Junchi Liu , Qian Zhu , Linlin Ma , Yanfei Li","doi":"10.1016/j.molimm.2025.10.009","DOIUrl":"10.1016/j.molimm.2025.10.009","url":null,"abstract":"<div><h3>Background</h3><div>This research aimed to elucidate the roles of plasma secretory protein genes in mediating the comorbid effects between hepatocellular carcinoma (HCC) and heart failure (HF).</div></div><div><h3>Methods</h3><div>A comprehensive analysis utilizing Weighted Gene Co-expression Network Analysis (WGCNA), differential expression analysis, and advanced deep learning techniques was conducted to identify three plasma-secreted protein genes (Ficolin-3: FCN3, Fibroblast Activation Protein: FAP, High Mobility Group Box 2: HMGB2) as key players in the comorbid interplay between HCC and HF.</div></div><div><h3>Results</h3><div>Validation experiments confirmed the significant biological functions of these genes in disease pathogenesis. Additionally, dexamethasone and catechins were identified as promising candidates for pharmacological intervention in the prevention of HCC and HF.</div></div><div><h3>Conclusion</h3><div>These findings unveil potential mechanistic pathways of comorbidity between HCC and HF, providing novel biological markers and therapeutic targets for the prognostic evaluation and treatment of these conditions, with substantial implications for refining clinical diagnosis and therapeutic strategies.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 45-61"},"PeriodicalIF":3.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.molimm.2025.10.012
Shihan Yang , Jing Chen , Xiaoshuang Shi , Jiamin Wang , Letian Li , Shouwen Du , Chang Li
The urokinase-type plasminogen activator system (uPAs) consists of the urokinase-type plasminogen activator (uPA), its receptor (uPA receptor, uPAR) and the plasminogen activator inhibitor (PAI). Recent studies have revealed that, beyond its well-established roles in promoting fibrinolysis and degrading extracellular matrix (ECM) proteins—thereby regulating tissue repair and tumor metastasis—this system also plays a significant role in viral infections. Specifically, the uPAs modulates viral infection processes by regulating the expression and activity of uPA and uPAR, which are involved in inflammatory response modulation, immune cell migration, and the infiltration of inflammatory cells during tissue repair in the context of viral infections. In this review, we summarize the roles of uPAs in various viral infections, aiming to deepen our understanding of the contributions of each uPA component and provide insights into potential strategies for inhibiting viral infection processes.
{"title":"Role of the urokinase-type plasminogen activator system in viral infection and replication","authors":"Shihan Yang , Jing Chen , Xiaoshuang Shi , Jiamin Wang , Letian Li , Shouwen Du , Chang Li","doi":"10.1016/j.molimm.2025.10.012","DOIUrl":"10.1016/j.molimm.2025.10.012","url":null,"abstract":"<div><div>The urokinase-type plasminogen activator system (uPAs) consists of the urokinase-type plasminogen activator (uPA), its receptor (uPA receptor, uPAR) and the plasminogen activator inhibitor (PAI). Recent studies have revealed that, beyond its well-established roles in promoting fibrinolysis and degrading extracellular matrix (ECM) proteins—thereby regulating tissue repair and tumor metastasis—this system also plays a significant role in viral infections. Specifically, the uPAs modulates viral infection processes by regulating the expression and activity of uPA and uPAR, which are involved in inflammatory response modulation, immune cell migration, and the infiltration of inflammatory cells during tissue repair in the context of viral infections. In this review, we summarize the roles of uPAs in various viral infections, aiming to deepen our understanding of the contributions of each uPA component and provide insights into potential strategies for inhibiting viral infection processes.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 38-44"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145420402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neohesperidin, a natural flavonoid found in citrus plants, has been reported to exhibit anti-inflammatory and antioxidant activities. In this study, we investigated its therapeutic potential in an ovalbumin (OVA)-induced murine model of allergic asthma. Female BALB/c mice were sensitized and challenged with OVA, followed by intraperitoneal administration of neohesperidin at doses of 10 or 20 mg/kg. The primary assessments included airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage fluid (BALF), lung histopathology, immunohistochemical analysis, and evaluation of oxidative stress biomarkers. In parallel, BEAS-2B human bronchial epithelial cells were stimulated with IL-4 and TNF-α to assess the anti-inflammatory and antioxidant effects of neohesperidin in vitro. Neohesperidin significantly attenuated several pathological features of asthma, including AHR, inflammatory cell infiltration, goblet cell hyperplasia, and collagen deposition. It not only suppressed Th2 cytokine levels and pro-inflammatory mediators in BALF, but also enhanced the activity of antioxidant enzymes in the lungs. Moreover, neohesperidin downregulated COX-2 expression and upregulated HO-1 in lung tissues. In BEAS-2B cells, it inhibited the release of inflammatory cytokines, reduced reactive oxygen species production, and decreased monocyte adhesion. Taken together, these findings suggest that neohesperidin possesses immunomodulatory and antioxidant properties that contribute to the attenuation of airway inflammation and remodeling in allergic asthma. These results indicate that neohesperidin is a promising natural compound with therapeutic potential for asthma treatment.
{"title":"Neohesperidin ameliorates airway remodeling through suppressed airway inflammation and oxidative stress in ovalbumin-sensitized mice","authors":"Shu-Chen Cheng , Chian-Jiun Liou , Ya-Ling Chen , Li-Wen Fang , Tse-Hung Huang , Wen-Chung Huang","doi":"10.1016/j.molimm.2025.10.011","DOIUrl":"10.1016/j.molimm.2025.10.011","url":null,"abstract":"<div><div>Neohesperidin, a natural flavonoid found in citrus plants, has been reported to exhibit anti-inflammatory and antioxidant activities. In this study, we investigated its therapeutic potential in an ovalbumin (OVA)-induced murine model of allergic asthma. Female BALB/c mice were sensitized and challenged with OVA, followed by intraperitoneal administration of neohesperidin at doses of 10 or 20 mg/kg. The primary assessments included airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage fluid (BALF), lung histopathology, immunohistochemical analysis, and evaluation of oxidative stress biomarkers. In parallel, BEAS-2B human bronchial epithelial cells were stimulated with IL-4 and TNF-α to assess the anti-inflammatory and antioxidant effects of neohesperidin <em>in vitro</em>. Neohesperidin significantly attenuated several pathological features of asthma, including AHR, inflammatory cell infiltration, goblet cell hyperplasia, and collagen deposition. It not only suppressed Th2 cytokine levels and pro-inflammatory mediators in BALF, but also enhanced the activity of antioxidant enzymes in the lungs. Moreover, neohesperidin downregulated COX-2 expression and upregulated HO-1 in lung tissues. In BEAS-2B cells, it inhibited the release of inflammatory cytokines, reduced reactive oxygen species production, and decreased monocyte adhesion. Taken together, these findings suggest that neohesperidin possesses immunomodulatory and antioxidant properties that contribute to the attenuation of airway inflammation and remodeling in allergic asthma. These results indicate that neohesperidin is a promising natural compound with therapeutic potential for asthma treatment.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 27-37"},"PeriodicalIF":3.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145384260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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