Molecular immunology最新文献_第4页

Silibinin, a PLC-β3 inhibitor, inhibits mast cell activation and alleviates OVA-induced asthma

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.molimm.2025.01.009

Tzu-Ting Chen , Juan-Cheng Yang , Guan-Yu Chen , Yun-Hao Dai , Xiang Zhang , Hong-Lin Chan , Tim CC Lin , Yang-Chang Wu

The immunoglobulin E (IgE) receptor FcεRI (Fc epsilon RI) plays a crucial role in allergic reactions. Recent studies have indicated that the interaction between FcεRIβ and the downstream protein phospholipase C beta 3 (PLCβ3) leads to the production of inflammatory cytokines. The aim of this study was to develop small molecules that inhibit the protein–protein interactions between FcεRIβ and PLCβ3 to treat allergic inflammation. Additionally, PLCβ3 has emerged as a potential target protein for treating allergic inflammation. In this study, we employed a virtual screening technique to search the Taiwan Traditional Chinese Medicine Database, followed by a second screening using absorption, distribution, metabolism, excretion, and toxicity (ADMET). Among the compounds screened, silibinin exhibited the best performance, forming strong hydrogen bond interactions with residues of PLCβ3, with a binding free energy of −119.277 kcal/mol. Therefore, silibinin effectively blocked the interaction between FcεRIβ and PLCβ3. Silibinin reduced the production of allergic inflammatory cytokines, including cytokine-induced neutrophil chemoattractant 2a (CINC-2a), interleukin-2 (IL-2), cytokine-induced neutrophil chemoattractant 1 (CINC-1), interleukin 1α (IL-1α), macrophage inflammatory protein 3 alpha (MIP3α), interferon γ (IFN-γ), activin A, granulocyte macrophage colony stimulating factor (GM-CSF), intercellular adhesion molecule-1 (ICAM-1), interleukin 4 (IL-4), interleukin 13 (IL-13), Fas ligand (FasL) and tumor necrosis factor alpha (TNF-α), without inducing cytotoxicity. Furthermore, in studies of IgE-mediated allergic responses, silibinin also decreased the expression of surface IgE receptors (FcεRIs). Moreover, silibinin effectively alleviated allergen-induced asthma responses and reduced the infiltration of inflammatory immune cells into the lungs of an OVA-induced allergic airway inflammation mouse model. Taken together, these results demonstrate the potential antiallergic mechanism of silibinin both in vitro and in vivo, making it a promising candidate for the development of asthma therapeutics.

{"title":"Silibinin, a PLC-β3 inhibitor, inhibits mast cell activation and alleviates OVA-induced asthma","authors":"Tzu-Ting Chen , Juan-Cheng Yang , Guan-Yu Chen , Yun-Hao Dai , Xiang Zhang , Hong-Lin Chan , Tim CC Lin , Yang-Chang Wu","doi":"10.1016/j.molimm.2025.01.009","DOIUrl":"10.1016/j.molimm.2025.01.009","url":null,"abstract":"<div><div>The immunoglobulin E (IgE) receptor FcεRI (Fc epsilon RI) plays a crucial role in allergic reactions. Recent studies have indicated that the interaction between FcεRIβ and the downstream protein phospholipase C beta 3 (PLCβ3) leads to the production of inflammatory cytokines. The aim of this study was to develop small molecules that inhibit the protein–protein interactions between FcεRIβ and PLCβ3 to treat allergic inflammation. Additionally, PLCβ3 has emerged as a potential target protein for treating allergic inflammation. In this study, we employed a virtual screening technique to search the Taiwan Traditional Chinese Medicine Database, followed by a second screening using absorption, distribution, metabolism, excretion, and toxicity (ADMET). Among the compounds screened, silibinin exhibited the best performance, forming strong hydrogen bond interactions with residues of PLCβ3, with a binding free energy of −119.277 kcal/mol. Therefore, silibinin effectively blocked the interaction between FcεRIβ and PLCβ3. Silibinin reduced the production of allergic inflammatory cytokines, including cytokine-induced neutrophil chemoattractant 2a (CINC-2a), interleukin-2 (IL-2), cytokine-induced neutrophil chemoattractant 1 (CINC-1), interleukin 1α (IL-1α), macrophage inflammatory protein 3 alpha (MIP3α), interferon γ (IFN-γ), activin A, granulocyte macrophage colony stimulating factor (GM-CSF), intercellular adhesion molecule-1 (ICAM-1), interleukin 4 (IL-4), interleukin 13 (IL-13), Fas ligand (FasL) and tumor necrosis factor alpha (TNF-α), without inducing cytotoxicity. Furthermore, in studies of IgE-mediated allergic responses, silibinin also decreased the expression of surface IgE receptors (FcεRIs). Moreover, silibinin effectively alleviated allergen-induced asthma responses and reduced the infiltration of inflammatory immune cells into the lungs of an OVA-induced allergic airway inflammation mouse model. Taken together, these results demonstrate the potential antiallergic mechanism of silibinin both in vitro and in vivo, making it a promising candidate for the development of asthma therapeutics.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"178 ","pages":"Pages 76-86"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052492","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}

引用次数: 0

Genetically engineered bacteria expressing IL-34 alleviate DSS-induced experimental colitis by promoting tight junction protein expression in intestinal mucosal epithelial cells

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.molimm.2025.01.008

Weijie Chen , Tongtong Zhou , Yicun Liu , Leilei Luo , Yujing Ye , Lixian Wei , Jian Chen , Zhaolian Bian

Background

The intestinal mucosa of ulcerative colitis patients expresses high levels of interleukin 34, and mice lacking IL-34 have more severe DSS-induced experimental colitis. There are no studies on the effects of directly upregulating intestinal IL-34 on experimental colitis in mice.

Methods

The bacteria EcN/CSF-1 and EcN/IL-34, which express CSF-1 and IL-34, respectively, were genetically engineered from Escherichia coli Nissle 1917 (EcN). Colitis mice received daily gavage of sterile PBS buffer, empty plasmid E. coli (EcN/WT), EcN/CSF-1, or EcN/IL-34. Each group of mice was assessed for body mass, clinical signs, DAI, intestinal mucosal permeability, pathological, and immunohistological changes. In vitro, NCM460 cells were treated with CSF-1 or IL-34 recombinant proteins in the presence of signaling pathway inhibitors to evaluate tight junction protein expression. Additionally, intestinal mucosal epithelial cells isolated from active UC patients were analyzed for IL-34 and tight junction protein levels.

Results

DSS-induced colitis mice are protected by EcN/IL-34 gavage. Pathological results showed that EcN/IL-34 group colonic histological injury was significantly improved and tight junction protein ZO-1 and Occludin expression increased. In NCM460 cells, IL-34 also increased tight junction protein expression. More importantly, expression of IL-34 was positively correlated with the level of tight junction protein expression in epithelial cells of UC patients.

Conclusion

EcN/IL-34 can directly act on damaged intestinal mucosa, up-regulate IL-34 expression, and promote tight junction protein expression in intestinal mucosal epithelial cells to alleviate experimental colitis in mice. IL-34 may be a potential therapeutic target for ulcerative colitis, and genetically engineered bacteria carrying the cytokine may offer new ideas for treating UC.

{"title":"Genetically engineered bacteria expressing IL-34 alleviate DSS-induced experimental colitis by promoting tight junction protein expression in intestinal mucosal epithelial cells","authors":"Weijie Chen , Tongtong Zhou , Yicun Liu , Leilei Luo , Yujing Ye , Lixian Wei , Jian Chen , Zhaolian Bian","doi":"10.1016/j.molimm.2025.01.008","DOIUrl":"10.1016/j.molimm.2025.01.008","url":null,"abstract":"<div><h3>Background</h3><div>The intestinal mucosa of ulcerative colitis patients expresses high levels of interleukin 34, and mice lacking IL-34 have more severe DSS-induced experimental colitis. There are no studies on the effects of directly upregulating intestinal IL-34 on experimental colitis in mice.</div></div><div><h3>Methods</h3><div>The bacteria EcN/CSF-1 and EcN/IL-34, which express CSF-1 and IL-34, respectively, were genetically engineered from <em>Escherichia coli</em> Nissle 1917 (EcN). Colitis mice received daily gavage of sterile PBS buffer, empty plasmid E. coli (EcN/WT), EcN/CSF-1, or EcN/IL-34. Each group of mice was assessed for body mass, clinical signs, DAI, intestinal mucosal permeability, pathological, and immunohistological changes. In vitro, NCM460 cells were treated with CSF-1 or IL-34 recombinant proteins in the presence of signaling pathway inhibitors to evaluate tight junction protein expression. Additionally, intestinal mucosal epithelial cells isolated from active UC patients were analyzed for IL-34 and tight junction protein levels.</div></div><div><h3>Results</h3><div>DSS-induced colitis mice are protected by EcN/IL-34 gavage. Pathological results showed that EcN/IL-34 group colonic histological injury was significantly improved and tight junction protein ZO-1 and Occludin expression increased. In NCM460 cells, IL-34 also increased tight junction protein expression. More importantly, expression of IL-34 was positively correlated with the level of tight junction protein expression in epithelial cells of UC patients.</div></div><div><h3>Conclusion</h3><div>EcN/IL-34 can directly act on damaged intestinal mucosa, up-regulate IL-34 expression, and promote tight junction protein expression in intestinal mucosal epithelial cells to alleviate experimental colitis in mice. IL-34 may be a potential therapeutic target for ulcerative colitis, and genetically engineered bacteria carrying the cytokine may offer new ideas for treating UC.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"178 ","pages":"Pages 64-75"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047358","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}

引用次数: 0

Screening for immunodominant epitopes of SARS-CoV-2 based on CD8+ T cell responses from individuals with HLA-A homozygous alleles

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.molimm.2025.01.010

Rui He , Lingxin Meng , Yuting Sun , Jingsong Wang , Shufeng Wang , Yueping Liu , Lei Fei , Zhongfang Wang , Qinggao Zhang , Yuzhang Wu , Yongwen Chen , Bo Diao

Purpose

SARS-CoV-2-specific CD8⁺ cytotoxic T lymphocytes (CTLs) are crucial in viral clearance, disease progression, and reinfection control. However, numerous SARS-CoV-2 immunodominant CTL epitopes theoretically are still unidentified due to the genetic polymorphism of human leukocyte antigen class I (HLA-I) molecules.

Methods

The CTL epitopes of SARS-CoV-2 were predicted by the epitope affinity and immunogenicity prediction platforms: the NetMHCpan and the PromPPD. Individuals with HLA-A homozygous alleles were screened from 252 COVID-19 vaccinees, including the Ad5-nCoV vaccine (CanSino, n = 183) and the CoronaVac inactivated vaccine (Sinovac, n = 69) using MiSeqDx™ generation sequencing, and their PBMCs were further stimulated by the predicted peptides to screen the immunodominant epitopes according to the secretion of IFN-γ from CD8⁺ T cells. Peptide-MHC tetramers were constructed and used to detect the frequency of antigen specific CTLs in vivo.

Results

Individuals with HLA-A homozygous alleles including HLA-A*01 (n = 1), -A*02 (n = 9), - A*03 and -A*11 (n = 12), and -A*24 (n = 7) supertypes were selected. Twelve immunodominant CTL epitopes for these HLA-A allotypes were finally screened based on the frequency of IFN-γ⁺CD8⁺ T cells in homozygous individuals. The SARS-CoV-2 specific CTLs from Omicron variant infected patients were successfully evaluated by these novel peptide-HLA tetramers.

Conclusion

A set of immunodominant CTL epitopes of SARS-CoV-2 was identified, and the antigen-specific CD8⁺ T cells in viral infected patients or COVID-19 vaccinees could be rapidly detected by a mixture of the peptide-MHC tetramers.

{"title":"Screening for immunodominant epitopes of SARS-CoV-2 based on CD8+ T cell responses from individuals with HLA-A homozygous alleles","authors":"Rui He , Lingxin Meng , Yuting Sun , Jingsong Wang , Shufeng Wang , Yueping Liu , Lei Fei , Zhongfang Wang , Qinggao Zhang , Yuzhang Wu , Yongwen Chen , Bo Diao","doi":"10.1016/j.molimm.2025.01.010","DOIUrl":"10.1016/j.molimm.2025.01.010","url":null,"abstract":"<div><h3>Purpose</h3><div>SARS-CoV-2-specific CD8<sup>+</sup> cytotoxic T lymphocytes (CTLs) are crucial in viral clearance, disease progression, and reinfection control. However, numerous SARS-CoV-2 immunodominant CTL epitopes theoretically are still unidentified due to the genetic polymorphism of human leukocyte antigen class I (HLA-I) molecules.</div></div><div><h3>Methods</h3><div>The CTL epitopes of SARS-CoV-2 were predicted by the epitope affinity and immunogenicity prediction platforms: the NetMHCpan and the PromPPD. Individuals with HLA-A homozygous alleles were screened from 252 COVID-19 vaccinees, including the Ad5-nCoV vaccine (CanSino, n = 183) and the CoronaVac inactivated vaccine (Sinovac, n = 69) using MiSeqDx™ generation sequencing, and their PBMCs were further stimulated by the predicted peptides to screen the immunodominant epitopes according to the secretion of IFN-γ from CD8<sup>+</sup> T cells. Peptide-MHC tetramers were constructed and used to detect the frequency of antigen specific CTLs <em>in vivo</em>.</div></div><div><h3>Results</h3><div>Individuals with HLA-A homozygous alleles including HLA-A*01 (n = 1), -A*02 (n = 9), - A*03 and -A*11 (n = 12), and -A*24 (n = 7) supertypes were selected. Twelve immunodominant CTL epitopes for these HLA-A allotypes were finally screened based on the frequency of IFN-γ<sup>+</sup>CD8<sup>+</sup> T cells in homozygous individuals. The SARS-CoV-2 specific CTLs from Omicron variant infected patients were successfully evaluated by these novel peptide-HLA tetramers.</div></div><div><h3>Conclusion</h3><div>A set of immunodominant CTL epitopes of SARS-CoV-2 was identified, and the antigen-specific CD8<sup>+</sup> T cells in viral infected patients or COVID-19 vaccinees could be rapidly detected by a mixture of the peptide-MHC tetramers.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"178 ","pages":"Pages 52-63"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047359","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}

引用次数: 0

Immunological characteristics of peripheral T cells as prognostic markers for Camrelizumab and Apatinib combination therapy in advanced squamous non-small-cell lung cancer

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.molimm.2025.01.011

Liangliang Wu , Xiaoyu Zhi , Shengzhi Xie , Keren Li , Man Chen , Gong Li , Qiyan Wu , Shunchang Jiao , Jinliang Wang , Tianyi Liu

Purpose

To determine the characteristic changes of peripheral blood T cells and identify potential biomarkers that associated with the clinical efficacy of combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous non-small cell lung cancer (NSCLC).

Methods

We performed a comprehensive immunological assessment of peripheral blood mononuclear cell samples from advanced squamous NSCLC patients before and after combination of immunotherapy (Camrelizumab) and anti-angiogenic therapy (Apatinib) using spectral flow cytometry. Correlations between these immunological features and clinical efficacy were analyzed.

Results

Our findings revealed that, following two treatment cycles, the concentration of type 1 T helper (Th1) cells in the peripheral circulation was significantly higher in the responder group than in the non-responder group, correlating with a statistically significant improvement in survival outcomes. Post-treatment, CD137 expression within Th1 cells in the responders, whereas TIM-3 expression was significantly reduced. In the validation cohort, elevated CD4⁺ CXCR3⁺ CD137⁺ cells in the peripheral blood were associated with a positive clinical reaction to the treatment and extended survival.

Conclusions

Our findings suggest that peripheral blood circulating CD4⁺ CXCR3⁺ CD137⁺ cells serve as biomarkers of response to combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous NSCLC, providing potential guidance for improving clinical outcomes.

{"title":"Immunological characteristics of peripheral T cells as prognostic markers for Camrelizumab and Apatinib combination therapy in advanced squamous non-small-cell lung cancer","authors":"Liangliang Wu , Xiaoyu Zhi , Shengzhi Xie , Keren Li , Man Chen , Gong Li , Qiyan Wu , Shunchang Jiao , Jinliang Wang , Tianyi Liu","doi":"10.1016/j.molimm.2025.01.011","DOIUrl":"10.1016/j.molimm.2025.01.011","url":null,"abstract":"<div><h3>Purpose</h3><div>To determine the characteristic changes of peripheral blood T cells and identify potential biomarkers that associated with the clinical efficacy of combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous non-small cell lung cancer (NSCLC).</div></div><div><h3>Methods</h3><div>We performed a comprehensive immunological assessment of peripheral blood mononuclear cell samples from advanced squamous NSCLC patients before and after combination of immunotherapy (Camrelizumab) and anti-angiogenic therapy (Apatinib) using spectral flow cytometry. Correlations between these immunological features and clinical efficacy were analyzed.</div></div><div><h3>Results</h3><div>Our findings revealed that, following two treatment cycles, the concentration of type 1 T helper (Th1) cells in the peripheral circulation was significantly higher in the responder group than in the non-responder group, correlating with a statistically significant improvement in survival outcomes. Post-treatment, CD137 expression within Th1 cells in the responders, whereas TIM-3 expression was significantly reduced. In the validation cohort, elevated CD4<sup>+</sup> CXCR3<sup>+</sup> CD137<sup>+</sup> cells in the peripheral blood were associated with a positive clinical reaction to the treatment and extended survival.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that peripheral blood circulating CD4<sup>+</sup> CXCR3<sup>+</sup> CD137<sup>+</sup> cells serve as biomarkers of response to combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous NSCLC, providing potential guidance for improving clinical outcomes.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"178 ","pages":"Pages 87-96"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phenotypes of antigen-induced responses in guinea pigs: Beyond the asthma model

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-01-31 DOI: 10.1016/j.molimm.2025.01.014

Marisol Álvarez-González , Ivonne Pacheco-Alba , Paola Moreno-Álvarez , Lizbeth Rogel-Velasco , Silvia Guerrero-Clorio , Angélica Flores-Flores , Mariana Téllez-Araiza , Juana Arellano-García , Angel Quevedo-Razo , Angélica Flores-Martínez , Blanca Bazán-Perkins

Asthma is a heterogeneous and variable disease. In an allergic asthma model using guinea pigs (GPs), we identified three distinct phenotypes: those always showing an obstructive response (R), those never responding (NR), and those sometimes responding (VR). We aimed to assess and compare the functional and immunological characteristics of these groups. GPs were sensitized and challenged with ovalbumin (OVA) every 10 days in a plethysmographic chamber to measure the maximum obstructive response. The control group was sensitized and challenged with saline. Control and NR GPs never duplicated baseline obstruction values. At least three antigenic challenges were needed to identify each phenotype. None of the groups showed late responses. Analysis of at least six antigenic challenges in 125 GPs revealed that 48 % were R, 20 % NR, 29 % VR, and 8 % died from anaphylactic shock. R GPs did not develop antigenic tolerance. During the third or twelfth challenges, we evaluated antigen-induced airway reactivity to histamine: R GPs consistently showed hyperreactivity, NR showed hyperreactivity only on the third challenge, while VR and control groups never showed hyperreactivity. Serum levels of anti-OVA IgE and IgG1 were elevated in all groups compared to controls. IL-4 levels in the lungs and eosinophils counts in bronchoalveolar lavage fluid (BALF) of R and VR were higher than to controls and NR. The number of mast cells in the airway wall also increased in R and VR compared to controls. IFN-γ levels were similar across all groups on the third challenge but increased significantly in NR on the twelfth challenge compared to the other groups. Neutrophil counts in BALF increased in R and VR, and in NR but only at the twelfth challenge compared to controls. Our findings suggest that R and VR guinea pigs serve as valid models for asthma, with VR representing a distinct phenotype characterized by variability and lack of hyperreactivity. Conversely, NR guinea pigs, despite their high IgE and anti-OVA IgG1 levels and hyperresponsiveness at the third challenge, do not align with typical asthma characteristics.

{"title":"Phenotypes of antigen-induced responses in guinea pigs: Beyond the asthma model","authors":"Marisol Álvarez-González , Ivonne Pacheco-Alba , Paola Moreno-Álvarez , Lizbeth Rogel-Velasco , Silvia Guerrero-Clorio , Angélica Flores-Flores , Mariana Téllez-Araiza , Juana Arellano-García , Angel Quevedo-Razo , Angélica Flores-Martínez , Blanca Bazán-Perkins","doi":"10.1016/j.molimm.2025.01.014","DOIUrl":"10.1016/j.molimm.2025.01.014","url":null,"abstract":"<div><div>Asthma is a heterogeneous and variable disease. In an allergic asthma model using guinea pigs (GPs), we identified three distinct phenotypes: those always showing an obstructive response (R), those never responding (NR), and those sometimes responding (VR). We aimed to assess and compare the functional and immunological characteristics of these groups. GPs were sensitized and challenged with ovalbumin (OVA) every 10 days in a plethysmographic chamber to measure the maximum obstructive response. The control group was sensitized and challenged with saline. Control and NR GPs never duplicated baseline obstruction values. At least three antigenic challenges were needed to identify each phenotype. None of the groups showed late responses. Analysis of at least six antigenic challenges in 125 GPs revealed that 48 % were R, 20 % NR, 29 % VR, and 8 % died from anaphylactic shock. R GPs did not develop antigenic tolerance. During the third or twelfth challenges, we evaluated antigen-induced airway reactivity to histamine: R GPs consistently showed hyperreactivity, NR showed hyperreactivity only on the third challenge, while VR and control groups never showed hyperreactivity. Serum levels of anti-OVA IgE and IgG1 were elevated in all groups compared to controls. IL-4 levels in the lungs and eosinophils counts in bronchoalveolar lavage fluid (BALF) of R and VR were higher than to controls and NR. The number of mast cells in the airway wall also increased in R and VR compared to controls. IFN-γ levels were similar across all groups on the third challenge but increased significantly in NR on the twelfth challenge compared to the other groups. Neutrophil counts in BALF increased in R and VR, and in NR but only at the twelfth challenge compared to controls. Our findings suggest that R and VR guinea pigs serve as valid models for asthma, with VR representing a distinct phenotype characterized by variability and lack of hyperreactivity. Conversely, NR guinea pigs, despite their high IgE and anti-OVA IgG1 levels and hyperresponsiveness at the third challenge, do not align with typical asthma characteristics.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"179 ","pages":"Pages 1-8"},"PeriodicalIF":3.2,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075082","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}

引用次数: 0

METTL3/YTHDF1-mediated m6A modification stabilizes USP12 to deubiquitinate FOXO3 and promote apoptosis in sepsis-induced myocardial dysfunction METTL3/ ythdf1介导的m6A修饰稳定USP12使FOXO3去泛素化并促进脓毒症诱导的心肌功能障碍的凋亡。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-01-01 DOI: 10.1016/j.molimm.2024.12.001

Zhiping Wang , Simiao Sun , Lili Huang , Xinlong Chen , Huifen Xu , Hongwei Ma , Mingbing Xiao , Linhua Wang

Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication primarily driven by inflammation, yet its molecular mechanisms remain unclear. In this study, we identified significant upregulation of the m⁶A methyltransferase METTL3 (methyltransferase-like 3), the m⁶A reader protein YTHDF1 (YTH N6-methyladenosine RNA binding protein 1), as well as increased expression levels of USP12 (ubiquitin-specific peptidase 12), FOXO3 (forkhead box O3), and key molecules in the intrinsic apoptotic pathway, PUMA (p53 upregulated modulator of apoptosis) and BAX (Bcl-2-associated X), through proteomic profiling in an LPS (Lipopolysaccharide)-induced SIMD mouse model. In vitro and in vivo experiments demonstrated that METTL3 and YTHDF1 regulated USP12 mRNA expression and stability through m⁶A modification. Elevated USP12 interacted with FOXO3, preventing its ubiquitin-mediated degradation, which enhanced FOXO3 binding to the PUMA promoter, leading to upregulation of PUMA. PUMA upregulation initiated the intrinsic apoptotic pathway, activating downstream BAX, Apaf1 (apoptotic protease-activating factor 1), and Caspases, ultimately driving SIMD. Inhibition of METTL3 (with STM2457), YTHDF1 (with Ebselen), or PUMA (with CLZ-8) significantly suppressed intrinsic apoptosis and alleviated SIMD symptoms. These findings underscore the critical role of METTL3/YTHDF1-dependent m⁶A modification in modulating the USP12-FOXO3-PUMA-BAX-Apaf1-Caspases signaling axis in SIMD, and suggest that targeting this pathway may offer a potential therapeutic strategy for SIMD.

脓毒症诱导心肌功能障碍（SIMD）是一种主要由炎症引起的危及生命的并发症，其分子机制尚不清楚。在本研究中，我们发现m6A甲基转移酶METTL3（甲基转移酶样3）、m6A解读蛋白YTHDF1 （YTH n6 -甲基腺苷RNA结合蛋白1）显著上调，USP12（泛素特异性肽酶12）、FOXO3（叉头盒O3）以及内在凋亡通路关键分子PUMA （p53上调的凋亡调节剂）和BAX （bcl -2相关X）表达水平升高。通过LPS（脂多糖）诱导的SIMD小鼠模型的蛋白质组学分析。体外和体内实验表明，METTL3和YTHDF1通过m6A修饰调节USP12 mRNA的表达和稳定性。升高的USP12与FOXO3相互作用，阻止其泛素介导的降解，从而增强FOXO3与PUMA启动子的结合，导致PUMA的上调。PUMA上调启动内在凋亡通路，激活下游BAX、Apaf1（凋亡蛋白酶激活因子1）和Caspases，最终驱动SIMD。抑制METTL3（与STM2457联合）、YTHDF1（与Ebselen联合）或PUMA（与CLZ-8联合）可显著抑制内在凋亡并缓解SIMD症状。这些发现强调了METTL3/ ythdf1依赖性m6A修饰在SIMD中调节USP12-FOXO3-PUMA-BAX-Apaf1-Caspases信号轴中的关键作用，并表明靶向该途径可能为SIMD提供潜在的治疗策略。

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引用次数: 0

LincR-PPP2R5C regulates the PP2A signaling pathway in the macrophage-myofibroblast transition in a mouse model of epidural fibrosis 在硬膜外纤维化小鼠模型中，LincR-PPP2R5C调控巨噬细胞-肌成纤维细胞转化过程中的PP2A信号通路。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-01-01 DOI: 10.1016/j.molimm.2024.12.006

Jinpeng Sun , Mohan Shi , Rui Mei , Youpeng Zhao , Yue Huang , Zeyuan Song , Feng Hua , Mingshun Zhang , Jun Liu

Low back pain after spine surgery is a major complication due to excessive epidural fibrosis, which compresses the lumbar nerve. Macrophage–myofibroblast transition (MMT) promoted epidural fibrosis in a mouse laminectomy model. Previously, we demonstrated that LincR-PPP2R5C regulated CD4 + T-cell differentiation. Here, we aimed to explore the roles and mechanisms of LincR-PPP2R5C in macrophages in epidural fibrosis. In M2 macrophages, the level of LincR-PPP2R5C was significantly decreased. Upon overexpression, LincR-PPP2R5C induced M1-macrophage polarization and reduced MMT. In contrast, LincR-PPP2R5C deficiency promoted M2-macrophage polarization and increased MMT. Mechanistically, LincR-PPP2R5C modulated the expression of α-SMA in macrophages via the PP2A signaling pathway. In vivo, LincR-PPP2R5C deficiency aggravated epidural fibrosis by enhancing MMT in a mouse model of laminectomy, and this effect was abolished in mice with macrophage depletion. Our study shed light on the effects of LincR-PPP2R5C on macrophage differentiation and MMT in epidural fibrosis.

脊柱手术后腰痛是一个主要的并发症，由于过度硬膜外纤维化，压迫腰神经。巨噬细胞-肌成纤维细胞转化（MMT）促进小鼠椎板切除术模型的硬膜外纤维化。先前，我们证明了LincR-PPP2R5C调节CD4 + t细胞分化。本研究旨在探讨LincR-PPP2R5C在巨噬细胞硬膜外纤维化中的作用及机制。在M2巨噬细胞中，LincR-PPP2R5C水平明显降低。过表达后，LincR-PPP2R5C诱导m1 -巨噬细胞极化，减少MMT。相反，LincR-PPP2R5C缺失促进了m2 -巨噬细胞极化，增加了MMT。机制上，LincR-PPP2R5C通过PP2A信号通路调节巨噬细胞α-SMA的表达。在体内，在椎板切除术小鼠模型中，LincR-PPP2R5C缺陷通过增强MMT加重硬膜外纤维化，而在巨噬细胞缺失小鼠中，这种作用被消除。我们的研究揭示了LincR-PPP2R5C对硬膜外纤维化中巨噬细胞分化和MMT的影响。

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引用次数: 0

Recognizing SARS-CoV-2 infection of nasopharyngeal tissue at the single-cell level by machine learning method 用机器学习方法在单细胞水平上识别鼻咽组织的 SARS-CoV-2 感染。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-01-01 DOI: 10.1016/j.molimm.2024.12.004

YuSheng Bao , QingLan Ma , Lei Chen , KaiYan Feng , Wei Guo , Tao Huang , Yu-Dong Cai

SARS-CoV-2 has posed serious global health challenges not only because of the high degree of virus transmissibility but also due to its severe effects on the respiratory system, such as inducing changes in multiple organs through the ACE2 receptor. This virus makes changes to gene expression at the single-cell level and thus to cellular functions and immune responses in a variety of cell types. Previous studies have not been able to resolve these mechanisms fully, and so our study tries to bridge knowledge gaps about the cellular responses under conditions of infection. We performed single-cell RNA-sequencing of nasopharyngeal swabs from COVID-19 patients and healthy controls. We assembled a dataset of 32,588 cells for 58 subjects for analysis. The data were sorted into eight cell types: ciliated, basal, deuterosomal, goblet, myeloid, secretory, squamous, and T cells. Using machine learning, including nine feature ranking algorithms and two classification algorithms, we classified the infection status of single cells and analyzed gene expression to pinpoint critical markers of SARS-CoV-2 infection. Our findings show distinct gene expression profiles between infected and uninfected cells across diverse cell types, with key indicators such as FKBP4, IFITM1, SLC35E1, CD200R1, MT-ATP6, KRT13, RBM15, and FTH1 illuminating unique immune responses and potential pathways for viral spread and immune evasion. The machine learning methods effectively differentiated between infected and non-infected cells, shedding light on the cellular heterogeneity of SARS-CoV-2 infection. The findings will improve our knowledge of the cellular dynamics of SARS-CoV-2.

SARS-CoV-2 给全球健康带来了严重挑战，这不仅是因为病毒的高度传播性，还因为它对呼吸系统的严重影响，如通过 ACE2 受体诱导多个器官发生变化。这种病毒会在单细胞水平上改变基因表达，从而改变多种细胞类型的细胞功能和免疫反应。以往的研究无法完全解析这些机制，因此我们的研究试图填补有关感染条件下细胞反应的知识空白。我们对 COVID-19 患者和健康对照者的鼻咽拭子进行了单细胞 RNA 测序。我们收集了 58 名受试者的 32,588 个细胞数据集进行分析。数据被分为八种细胞类型：纤毛细胞、基底细胞、脱细胞、鹅口疮细胞、髓样细胞、分泌细胞、鳞状细胞和 T 细胞。通过机器学习（包括九种特征排序算法和两种分类算法），我们对单个细胞的感染状态进行了分类，并分析了基因表达，以确定 SARS-CoV-2 感染的关键标志物。我们的研究结果表明，在不同类型的细胞中，感染细胞和未感染细胞的基因表达谱截然不同，FKBP4、IFITM1、SLC35E1、CD200R1、MT-ATP6、KRT13、RBM15 和 FTH1 等关键指标揭示了独特的免疫反应以及病毒传播和免疫逃避的潜在途径。机器学习方法有效地区分了感染和非感染细胞，揭示了 SARS-CoV-2 感染的细胞异质性。这些发现将增进我们对 SARS-CoV-2 细胞动态的了解。

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引用次数: 0

Shikonin hastens diabetic wound healing by inhibiting M1 macrophage polarisation through the MAPK signaling pathway 紫草素通过MAPK信号通路抑制M1巨噬细胞极化，促进糖尿病伤口愈合。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-01-01 DOI: 10.1016/j.molimm.2024.12.002

Banxin Luo , Xiaofeng Ding , Yue Hu , Meng Tian , Junchao Wu , Huan Shi , Xizi Lu , Xuefeng Xia , Wenxian Guan , Wencheng Jiang

Diabetes is an endocrine disorder characterized by abnormally elevated blood glucose levels. Diabetic patients often exhibit impaired wound healing capabilities, particularly in the lower limbs, which is one of the numerous complications of diabetes. This is a significant factor leading to recurrent inflammation, disability, and even amputation. The primary objective of this study is to explore the mechanism by which shikonin accelerates diabetic wound healing by modulating macrophage phenotypes, particularly its role in the MAPK signaling pathway. To this end, we used a diabetic rat model and analyzed the effects of shikonin on the wound healing process and macrophage polarization in both in vivo and in vitro experiments. Additionally, we used immunofluorescence staining and Western blot techniques to detect the expression levels of macrophage polarization markers and proteins related to the MAPK signaling pathway. The results verify that shikonin significantly accelerated wound healing in diabetic rats and inhibited the polarization of M1 macrophages, reducing the expression of pro-inflammatory factors, while promoting the polarization of M2 macrophages, increasing the expression of anti-inflammatory factors. This process was accompanied by the regulation of the MAPK signaling pathway, indicating that shikonin accelerates diabetic wound healing by regulating the MAPK signaling pathway to inhibit the inflammatory phenotype of macrophages, showing significant clinical application prospects.

糖尿病是一种以血糖水平异常升高为特征的内分泌紊乱。糖尿病患者经常表现出伤口愈合能力受损，特别是在下肢，这是糖尿病的众多并发症之一。这是导致复发性炎症、残疾甚至截肢的重要因素。本研究的主要目的是探讨紫草素通过调节巨噬细胞表型加速糖尿病伤口愈合的机制，特别是其在MAPK信号通路中的作用。为此，我们采用糖尿病大鼠模型，通过体内和体外实验分析了紫草素对创面愈合过程和巨噬细胞极化的影响。此外，我们使用免疫荧光染色和Western blot技术检测巨噬细胞极化标记物和MAPK信号通路相关蛋白的表达水平。结果证实，紫草素显著加速糖尿病大鼠创面愈合，抑制M1巨噬细胞极化，降低促炎因子表达，同时促进M2巨噬细胞极化，增加抗炎因子表达。这一过程伴随着MAPK信号通路的调控，说明紫草素通过调控MAPK信号通路，抑制巨噬细胞的炎症表型，从而加速糖尿病创面愈合，具有重要的临床应用前景。

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引用次数: 0

Baicalin-Geniposide glycosides inhibit PM2.5-induced brain damage in rats via the 5-LOX/LTB4 pathway 黄芩苷-京尼平苷苷通过5-LOX/LTB4途径抑制pm2.5诱导的大鼠脑损伤。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-01-01 DOI: 10.1016/j.molimm.2024.12.005

Jiahao Zhang , Lu Zhao , Andong Zhao , Tian Hu , Xuewei Zhou , Yuan Li , Jie Gong , Chuan Wang , Jiping Liu , Bin Wang

Background

PM2.5-induced brain damage is related to systemic inflammation and oxidative stress, which can be caused by PM2.5 acting directly on the brain or indirectly by stimulating inflammation in the peripheral nervous system; however, the underlying pathological mechanisms are still unclear. Baicalin (BC) and geniposide glycosides (GD) are natural products that may exert neuroprotective effects by reducing inflammatory responses and oxidative damage.

Methods

A mouse model of microglial polarization was established via in vitro exposure to PM2.5, and tracheal drip injection of PM2.5-suspended dust was used to simulate PM2.5-induced brain damage. The expression of polarization markers in mouse microglia, changes in the levels of inflammatory factors, and changes in memory, cerebral blood flow and 5-lipoxygenase/leukotriene B4 (5-LOX/LTB4) pathway proteins in a brain injury model rat were investigated via enzyme-linked immunosorbent assays, real-time fluorescence quantitative PCR and Western blotting techniques after baicalein-gardenia glycoside action.

Results

The most successful experimental animal model of PM2.5-induced brain damage in rats was achieved when the dye dose was 15 mg/kg and the dyeing time was 3 M. BC/GD is protective against PM2.5-induced brain damage in rats. Baicalin and gardenia ameliorate microglial activation and brain tissue inflammatory injury induced by PM2.5, and its protective effect is associated with the 5-LOX/LTB4 pathway.

Conclusions

Baicalin-Geniposide glycoside prevents PM2.5-induced brain injury by activating the 5-LOX/LTB4 pathway and inhibiting inflammation and microglial polarization to the M2 type.

背景：PM2.5引起的脑损伤与全身性炎症和氧化应激有关，可由PM2.5直接作用于大脑或通过刺激周围神经系统炎症间接引起；然而，潜在的病理机制尚不清楚。黄芩苷（Baicalin， BC）和京尼平苷（geniposide glycosides， GD）是一种天然产物，可能通过减少炎症反应和氧化损伤而发挥神经保护作用。方法：通过体外暴露于PM2.5建立小鼠小胶质细胞极化模型，并通过气管滴注PM2.5悬浮粉尘模拟PM2.5致脑损伤。采用酶联免疫吸附法、实时荧光定量PCR和Western blotting技术，研究黄芩苷-栀子苷作用后小鼠脑损伤模型大鼠小胶质细胞极化标记物的表达、炎症因子水平的变化、记忆、脑血流量和5-脂氧合酶/白三烯B4 （5-LOX/LTB4）通路蛋白的变化。结果：当染色剂量为15 mg/kg，染色时间为3 M时，获得了最成功的pm2.5致大鼠脑损伤实验动物模型。BC/GD对pm2.5引起的大鼠脑损伤具有保护作用。黄芩苷和栀子花可改善PM2.5诱导的小胶质细胞活化和脑组织炎症损伤，其保护作用可能与5-LOX/LTB4通路有关。结论：黄芩苷-京尼平苷通过激活5-LOX/LTB4通路，抑制炎症和小胶质细胞向M2型极化来预防pm2.5所致的脑损伤。

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