Cellular immunology最新文献

Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells 丁酸钠可预防脂多糖诱导的炎症，恢复人上皮Caco-2细胞紧密连接蛋白的表达。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104912

Jyotsana Bakshi, K.P. Mishra

The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.

在高海拔缺氧条件下，胃肠道容易受到损伤，导致胃肠道不适和肠屏障损伤。丁酸钠是一种短链脂肪酸，作为肠道代谢物存在，由于其作为免疫调节剂和恢复肠道屏障完整性的能力，已成为一种有前景的治疗剂。本研究旨在探讨丁酸钠对肠上皮细胞抗炎作用的机制。体外实验采用Caco-2上皮细胞和RAW 264.7巨噬细胞研究丁酸钠对脂多糖（LPS）诱导炎症的保护作用。细胞活力实验表明，1 mM （110.86 μg/mL）丁酸钠对体外培养的细胞无杀伤作用。用丁酸钠治疗可抑制lps刺激的巨噬细胞中活性氧水平和TNF-α的产生，表明其减轻炎症反应的功效。Western blot分析显示，丁酸钠能降低巨噬细胞中iNOS的表达。此外，丁酸钠还能逆转LPS诱导的Caco-2上皮细胞中HIF-1α、NLRP3、IL-1β和NF-kB的过表达，并抑制LPS刺激后IL-8的分泌。免疫细胞化学表明，丁酸钠增强Caco-2细胞中紧密连接蛋白occludin的表达，同时也恢复了由于LPS导致的Caco-2单层通透性下降。这些结果表明，丁酸钠可能通过抑制炎症介质和改善上皮屏障的完整性来影响免疫反应。了解肠道代谢物与宿主免疫反应之间复杂的相互作用可能有助于开发创新的治疗策略，以减轻高海拔环境下的肠道炎症。

{"title":"Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells","authors":"Jyotsana Bakshi, K.P. Mishra","doi":"10.1016/j.cellimm.2024.104912","DOIUrl":"10.1016/j.cellimm.2024.104912","url":null,"abstract":"<div><div>The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. <em>In vitro,</em> Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells <em>in vitro</em>. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104912"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Berberine shaping the tumor immune landscape via pyroptosis 小檗碱通过焦亡形成肿瘤免疫景观。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104908

Jinjin Xie , Xin Du , Yuke Li , Chengyu Wu , Rui Li , Mengnan Zhao , Sanjun Shi

Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4 T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4 T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.

焦亡是一种主要由Gasdermin家族蛋白介导的程序性细胞死亡（PCD），其中Gasdermin E （GSDME）被认为是一种肿瘤抑制基因。GSDME可以将免疫细胞招募到肿瘤微环境（tumor microenvironment， TME）并促进其作用。通过GSDME激活和增强适应性免疫是抗肿瘤治疗的潜在解决方案。本文报道了中药小分子小檗碱（berberine， BBR）作为GSDME激活剂，通过线粒体途径诱导caspase-3 (C-3)/GSDME途径介导的焦亡，改善肿瘤微环境的免疫抑制状态，从而促进抗肿瘤免疫。我们通过各种实验确定BBR对4个T1细胞的诱导凋亡作用，并通过体外共培养研究BBR诱导DCs成熟和巨噬细胞极化的免疫激活作用。采用斑马鱼胚胎毒性实验评价小檗碱的体内安全性。利用4只T1原位模型小鼠研究了BBR的体内抗肿瘤和免疫激活作用，结果表明BBR可以通过激活局部和全身免疫来消除原位肿瘤细胞。此外，我们观察到BBR显著抑制乳腺癌肺转移。综上所述，我们的研究结果表明，BBR作为GSDME激活剂通过诱导焦亡刺激局部和全身的抗肿瘤免疫反应，有效地阻止肿瘤的发展和转移。

{"title":"Berberine shaping the tumor immune landscape via pyroptosis","authors":"Jinjin Xie , Xin Du , Yuke Li , Chengyu Wu , Rui Li , Mengnan Zhao , Sanjun Shi","doi":"10.1016/j.cellimm.2024.104908","DOIUrl":"10.1016/j.cellimm.2024.104908","url":null,"abstract":"<div><div>Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4 T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture <em>in vitro</em>, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the <em>in vivo</em> safety of berberine. Furthermore, the <em>in vivo</em> antitumor and immune activation effects of BBR were investigated using 4 T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104908"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Bacteriophage derived dsRNA induces polarized activation of alveolar macrophages from Balb/c and C57Bl/6 mice in vitro in sex- and age-dependent manner 噬菌体来源的dsRNA诱导Balb/c和C57Bl/6小鼠肺泡巨噬细胞在体外以性别和年龄依赖的方式极化活化。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2025.104916

R. Dovhyi , A. Dvukhriadkina , K. Ostrovska , M. Rudyk , Irina Verhovcova , Kristine Vaivode , D. Pjanova , L. Ostapchenko , L. Skivka

Bacteriophage-derived dsRNA (bp-dsRNA), also known as Larifan, is a poly-functional and wide-spectrum antiviral medication with potent interferonogenic activity. In the lungs of golden Syrian hamsters infected with SARS-CoV-2, Larifan substantially reduces viral load and decreases infection-induced pathological lesion severity. Alveolar macrophages (AM) are key sentinel cells in the lung, which play an important role in antiviral innate immune responses and, at the same time, can trigger infection-associated hyper-inflammatory response. This study revealed that treatment with bp-dsRNA (Larifan) in vitro modulates the functional profile of AM from intact Balb/c and C57Bl/6 mice. The pattern of the drug response depends on the animal strain, age and sex. AM from Balb/c mice generated a weaker response to the preparation as compared to cells from C57Bl/6 mice. Most emphatic responses to the treatment with bf-dsRNA (Larifan) were registered in AM from old males of both BALB/c and C57BL/6 strains with the strongest in the latter. AM from old C57BL/6 females were less likely to be influenced by the preparation. In most cases, exposure to bf-dsRNA (Larifan) increased AM phagocytic activity and was more often accompanied by the stimulation of intracellular reactive oxygen species generation, than by its decrease. In most animal groups, treatment with bf-dsRNA (Larifan) did not affect significantly CD206 expression and down-regulated CD80 expression in AM. Taken together, our findings suggest that bf-dsRNA (Larifan) not so much stimulates the bivalent phenotype of AM, as restrains their hyper-inflammatory responses through the control of antigen-presentation while preserving functional signatures typical of patrolling tissue-resident macrophages.

噬菌体衍生的dsRNA (bp-dsRNA)，也被称为Larifan，是一种多功能广谱抗病毒药物，具有强干扰素活性。在感染SARS-CoV-2的金色叙利亚仓鼠肺中，拉里凡显著降低病毒载量，降低感染引起的病理病变严重程度。肺泡巨噬细胞（Alveolar macrophages， AM）是肺部关键的前哨细胞，在抗病毒先天免疫应答中发挥重要作用，同时可引发感染相关的超炎症反应。本研究表明，bp-dsRNA （Larifan）在体外可调节完整Balb/c和C57Bl/6小鼠AM的功能谱。药物反应的模式取决于动物的品系、年龄和性别。与来自C57Bl/6小鼠的细胞相比，来自Balb/c小鼠的AM对该制剂的反应较弱。BALB/c和C57BL/6菌株的老年男性AM对bf-dsRNA （Larifan）治疗的反应最强烈，后者最强。老年C57BL/6雌性的AM受制剂的影响较小。在大多数情况下，暴露于bf-dsRNA （Larifan）会增加AM的吞噬活性，并且通常伴随着细胞内活性氧生成的刺激，而不是其减少。在大多数动物组中，用bf-dsRNA （Larifan）治疗AM不显著影响CD206表达，并下调CD80表达。综上所述，我们的研究结果表明，bf-dsRNA （Larifan）并不会刺激AM的二价表型，而是通过控制抗原呈递来抑制AM的超炎症反应，同时保留巡逻组织内巨噬细胞的典型功能特征。

{"title":"Bacteriophage derived dsRNA induces polarized activation of alveolar macrophages from Balb/c and C57Bl/6 mice in vitro in sex- and age-dependent manner","authors":"R. Dovhyi , A. Dvukhriadkina , K. Ostrovska , M. Rudyk , Irina Verhovcova , Kristine Vaivode , D. Pjanova , L. Ostapchenko , L. Skivka","doi":"10.1016/j.cellimm.2025.104916","DOIUrl":"10.1016/j.cellimm.2025.104916","url":null,"abstract":"<div><div>Bacteriophage-derived dsRNA (bp-dsRNA), also known as Larifan, is a poly-functional and wide-spectrum antiviral medication with potent interferonogenic activity. In the lungs of golden Syrian hamsters infected with SARS-CoV-2, Larifan substantially reduces viral load and decreases infection-induced pathological lesion severity. Alveolar macrophages (AM) are key sentinel cells in the lung, which play an important role in antiviral innate immune responses and, at the same time, can trigger infection-associated hyper-inflammatory response. This study revealed that treatment with bp-dsRNA (Larifan) <em>in vitro</em> modulates the functional profile of AM from intact Balb/c and C57Bl/6 mice. The pattern of the drug response depends on the animal strain, age and sex. AM from Balb/c mice generated a weaker response to the preparation as compared to cells from C57Bl/6 mice. Most emphatic responses to the treatment with bf-dsRNA (Larifan) were registered in AM from old males of both BALB/c and C57BL/6 strains with the strongest in the latter. AM from old C57BL/6 females were less likely to be influenced by the preparation. In most cases, exposure to bf-dsRNA (Larifan) increased AM phagocytic activity and was more often accompanied by the stimulation of intracellular reactive oxygen species generation, than by its decrease. In most animal groups, treatment with bf-dsRNA (Larifan) did not affect significantly CD206 expression and down-regulated CD80 expression in AM. Taken together, our findings suggest that bf-dsRNA (Larifan) not so much stimulates the bivalent phenotype of AM, as restrains their hyper-inflammatory responses through the control of antigen-presentation while preserving functional signatures typical of patrolling tissue-resident macrophages.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104916"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells p2rx1阻断的中性粒细胞诱导CD8+ T细胞功能障碍，影响胃癌细胞的免疫逃逸。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104901

Yan Zhang , Fenglin Zhang , Zhi Liu , Min Li , Ge Wu , Hui Li

Background

Gastric cancer (GC) is one of the deadly malignancies of the gastrointestinal tract. Research has confirmed the linkage of P2RX1 with immune cell activation and tumor progression. This project focused on the impact of P2RX1 level in neutrophils on the efficacy of immune checkpoint inhibitor (ICI) treatment in GC.

Methods

Blood samples from 23 GC patients eligible for camrelizumab treatment were collected. Flow cytometry was carried out to analyze the proportion of P2RX1 in neutrophils. IHC was utilized to detect the expression level of PD-L1. We also evaluated the chemotaxis ability of neutrophils using a Transwell system, assessed the viability and apoptosis rate of GC cells using CCK-8 and flow cytometry, measured the proportions of CD8⁺PD-1⁺ and CD8⁺GZMB⁺ cells, determined the expression levels of IL-6, TNFα, IFN-γ, IL-8, IL-12, IL-1β, and GZMB by utilizing enzyme-linked immunosorbent assay (ELISA), and examined the expression levels of P2RX1 and PD-L1 using western blot (WB). By establishing a xenograft mouse model, we studied the impact of P2RX1-blocked neutrophils on the efficacy of ICI treatment in the GC microenvironment.

Results

In GC, clinical analysis revealed increased infiltration of P2RX1-lowly expressed neutrophil subsets and increased expression of PD-L1. In vitro experiments demonstrated that abnormal expression of P2RX1 affected neutrophil function. Furthermore, the blockage or knockdown of P2RX1 in neutrophils modulated CD8⁺ T cell function, promoting GC progression. In in vivo experiments, the blockage of P2RX1 in neutrophils inhibited the effectiveness of ICI treatment in the GC microenvironment.

Conclusion

This project validated that the loss of P2RX1 in neutrophils induces CD8⁺ T cell dysfunction and affects the GC development, indicating that P2RX1 may be an accurate biomarker for predicting ICI response, thus providing a theoretical basis for the clinical application of ICI.

背景：胃癌（GC）是胃肠道中致命的恶性肿瘤之一。研究证实 P2RX1 与免疫细胞活化和肿瘤进展有关。本项目重点研究中性粒细胞中P2RX1水平对免疫检查点抑制剂（ICI）治疗胃癌疗效的影响：方法：收集了23名符合康瑞珠单抗治疗条件的GC患者的血液样本。流式细胞术分析了中性粒细胞中 P2RX1 的比例。利用 IHC 检测 PD-L1 的表达水平。我们还使用 Transwell 系统评估了中性粒细胞的趋化能力，使用 CCK-8 和流式细胞术评估了 GC 细胞的存活率和凋亡率，测量了 CD8+PD-1+ 和 CD8+GZMB+ 细胞的比例、利用酶联免疫吸附试验（ELISA）测定 IL-6、TNFα、IFN-γ、IL-8、IL-12、IL-1β 和 GZMB 的表达水平，并利用 Western 印迹（WB）检测 P2RX1 和 PD-L1 的表达水平。通过建立异种移植小鼠模型，我们研究了 P2RX1 受体阻断的中性粒细胞对 ICI 治疗 GC 微环境疗效的影响：在 GC 中，临床分析显示 P2RX1 低表达的中性粒细胞亚群浸润增加，PD-L1 表达增加。体外实验表明，P2RX1 的异常表达会影响中性粒细胞的功能。此外，阻断或敲除中性粒细胞中的 P2RX1 会调节 CD8+ T 细胞的功能，促进 GC 的进展。在体内实验中，阻断中性粒细胞中的 P2RX1 会抑制 ICI 在 GC 微环境中的治疗效果：该项目验证了中性粒细胞中P2RX1的缺失会诱导CD8+ T细胞功能障碍并影响GC的发展，表明P2RX1可能是预测ICI反应的准确生物标志物，从而为ICI的临床应用提供了理论依据。

{"title":"P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells","authors":"Yan Zhang , Fenglin Zhang , Zhi Liu , Min Li , Ge Wu , Hui Li","doi":"10.1016/j.cellimm.2024.104901","DOIUrl":"10.1016/j.cellimm.2024.104901","url":null,"abstract":"<div><h3>Background</h3><div>Gastric cancer (GC) is one of the deadly malignancies of the gastrointestinal tract. Research has confirmed the linkage of P2RX1 with immune cell activation and tumor progression. This project focused on the impact of P2RX1 level in neutrophils on the efficacy of immune checkpoint inhibitor (ICI) treatment in GC.</div></div><div><h3>Methods</h3><div>Blood samples from 23 GC patients eligible for camrelizumab treatment were collected. Flow cytometry was carried out to analyze the proportion of P2RX1 in neutrophils. IHC was utilized to detect the expression level of PD-L1. We also evaluated the chemotaxis ability of neutrophils using a Transwell system, assessed the viability and apoptosis rate of GC cells using CCK-8 and flow cytometry, measured the proportions of CD8<sup>+</sup>PD-1<sup>+</sup> and CD8<sup>+</sup>GZMB<sup>+</sup> cells, determined the expression levels of IL-6, TNFα, IFN-γ, IL-8, IL-12, IL-1β, and GZMB by utilizing enzyme-linked immunosorbent assay (ELISA), and examined the expression levels of P2RX1 and PD-L1 using western blot (WB). By establishing a xenograft mouse model, we studied the impact of P2RX1-blocked neutrophils on the efficacy of ICI treatment in the GC microenvironment.</div></div><div><h3>Results</h3><div>In GC, clinical analysis revealed increased infiltration of P2RX1-lowly expressed neutrophil subsets and increased expression of PD-L1. <em>In vitro</em> experiments demonstrated that abnormal expression of P2RX1 affected neutrophil function. Furthermore, the blockage or knockdown of P2RX1 in neutrophils modulated CD8<sup>+</sup> T cell function, promoting GC progression. In <em>in vivo</em> experiments, the blockage of P2RX1 in neutrophils inhibited the effectiveness of ICI treatment in the GC microenvironment.</div></div><div><h3>Conclusion</h3><div>This project validated that the loss of P2RX1 in neutrophils induces CD8<sup>+</sup> T cell dysfunction and affects the GC development, indicating that P2RX1 may be an accurate biomarker for predicting ICI response, thus providing a theoretical basis for the clinical application of ICI.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104901"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Enhanced apoptosis and inflammation allied with autophagic and apoptotic Leishmania amastigotes in the seemingly undamaged ear skin of clinically affected dogs with canine visceral Leishmaniasis 在临床感染犬内脏利什曼病的犬耳皮肤中，与自噬和凋亡利什曼原虫无毛线虫相关的细胞凋亡和炎症增强。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104909

Barbara Laurice Araújo Verçosa , Maria Imaculada Muniz-Junqueira , Ana Lys Bezerra Barradas Mineiro , Maria Norma Melo , Anilton Cesar Vasconcelos

Programmed cell death plays a relevant role in the pathogenesis of visceral Leishmaniasis. Apoptosis selects suitable parasites, regulating parasite density, whereas autophagy eliminates pathogens. This study aimed to assess the inflammation and apoptosis in inflammatory cells and presents a unique description of the presence of autophagic and apoptotic Leishmania amastigotes in naturally Leishmania-infected dogs. Fragments from seemingly undamaged ear skin of sixteen Leishmania-infected dogs and seven uninfected dogs were evaluated through histomorphometry, ultrastructural, immunohistochemical and transmission electron microscopy (TEM) analyses. Leishmania amastigotes were present on seemingly undamaged ear skin only in clinically affected dogs. Parasite load, morphometrical parameters of inflammation and apoptotic index of inflammatory cells were higher in clinically affected animals and were related to clinical manifestations. Apoptotic index and morphometric parameters of the inflammatory infiltrate in undamaged ear skin were positively correlated with parasite load. Apoptotic and non-apoptotic Leishmania amastigotes were observed within neutrophils and macrophages. Leishmania amastigotes were positive for Bax, a marker for apoptosis, by immunohistochemistry. Morphological characteristics of apoptosis and autophagy in Leishmania amastigotes were observed only in phagocytes of clinically affected dogs. Positive correlations were found between histomorphometry and clinical manifestations. Our results showed that apoptosis and autophagy in Leishmania amastigotes may be related to both the increase in parasite load and apoptotic index in inflammatory cells, and with the intensity of the inflammatory response in clinically affected dogs. Thus, our study suggests that apoptotic and autophagy Leishmania within phagocytes may have facilitate the survival of the parasite and it appears to play an important role in the process of Leishmania infection.

程序性细胞死亡在内脏利什曼病的发病机制中起着相关作用。细胞凋亡选择合适的寄生虫，调节寄生虫密度，而自噬消除病原体。本研究旨在评估炎症细胞的炎症和凋亡，并对自然感染利什曼原虫的狗体内存在自噬和凋亡的利什曼原虫无鞭毛体进行独特的描述。对16只感染利什曼犬和7只未感染利什曼犬的耳部皮肤进行组织形态学、超微结构、免疫组织化学和透射电镜分析。利什曼原虫无鞭毛体只存在于临床感染犬的看似未受损的耳皮肤上。临床感染动物的寄生虫负荷、炎症形态计量参数和炎症细胞凋亡指数均较高，且与临床表现有关。未损伤耳部皮肤炎症浸润的凋亡指数和形态学参数与寄生虫负荷呈正相关。中性粒细胞和巨噬细胞内均可见凋亡和非凋亡利什曼原虫。免疫组化法检测利什曼原虫凋亡标志物Bax阳性。利什曼原虫凋亡和自噬的形态学特征仅在临床感染犬的吞噬细胞中观察到。组织形态学与临床表现呈正相关。我们的研究结果表明，利什曼原虫的凋亡和自噬可能与炎症细胞中寄生虫负荷和凋亡指数的增加有关，并与临床感染犬的炎症反应强度有关。因此，我们的研究表明，吞噬细胞内的凋亡和自噬利什曼原虫可能促进了寄生虫的生存，并在利什曼原虫感染过程中发挥了重要作用。

{"title":"Enhanced apoptosis and inflammation allied with autophagic and apoptotic Leishmania amastigotes in the seemingly undamaged ear skin of clinically affected dogs with canine visceral Leishmaniasis","authors":"Barbara Laurice Araújo Verçosa , Maria Imaculada Muniz-Junqueira , Ana Lys Bezerra Barradas Mineiro , Maria Norma Melo , Anilton Cesar Vasconcelos","doi":"10.1016/j.cellimm.2024.104909","DOIUrl":"10.1016/j.cellimm.2024.104909","url":null,"abstract":"<div><div>Programmed cell death plays a relevant role in the pathogenesis of visceral Leishmaniasis. Apoptosis selects suitable parasites, regulating parasite density, whereas autophagy eliminates pathogens. This study aimed to assess the inflammation and apoptosis in inflammatory cells and presents a unique description of the presence of autophagic and apoptotic <em>Leishmania</em> amastigotes in naturally <em>Leishmania-</em>infected dogs. Fragments from seemingly undamaged ear skin of sixteen <em>Leishmania</em>-infected dogs and seven uninfected dogs were evaluated through histomorphometry, ultrastructural, immunohistochemical and transmission electron microscopy (TEM) analyses. <em>Leishmania</em> amastigotes were present on seemingly undamaged ear skin only in clinically affected dogs. Parasite load, morphometrical parameters of inflammation and apoptotic index of inflammatory cells were higher in clinically affected animals and were related to clinical manifestations. Apoptotic index and morphometric parameters of the inflammatory infiltrate in undamaged ear skin were positively correlated with parasite load. Apoptotic and non-apoptotic <em>Leishmania</em> amastigotes were observed within neutrophils and macrophages. <em>Leishmania</em> amastigotes were positive for Bax, a marker for apoptosis, by immunohistochemistry. Morphological characteristics of apoptosis and autophagy in <em>Leishmania</em> amastigotes were observed only in phagocytes of clinically affected dogs. Positive correlations were found between histomorphometry and clinical manifestations. Our results showed that apoptosis and autophagy in <em>Leishmania</em> amastigotes may be related to both the increase in parasite load and apoptotic index in inflammatory cells, and with the intensity of the inflammatory response in clinically affected dogs. Thus, our study suggests that apoptotic and autophagy <em>Leishmania</em> within phagocytes may have facilitate the survival of the parasite and it appears to play an important role in the process of <em>Leishmania</em> infection.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104909"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The effect of tocilizumab treatment for skin fibrosis by inhibiting CD38+ macrophages in systemic sclerosis 托珠单抗通过抑制系统性硬化症中CD38+巨噬细胞治疗皮肤纤维化的作用。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104914

Hongzhen Chen , Dapeng Yang , Yirui Shi , Haolin Wu , Huiming Zhu , Tingting Jiang , Shu Liu , Dandan Wang

Background

Dermal and pulmonary fibrosis are the main clinical symptoms of systemic scleroderma (SSc), for which there are no effective therapeutic agents. Tocilizumab is thought to improve the symptoms of fibrosis, but the effect of tocilizumab on dermal fibrosis has not been explored. This study aims to investigate the therapeutic effect of tocilizumab on skin fibrosis by inhibiting CD38⁺ macrophages in the bleomycin-induced SSc mice model.

Methods

The 8-week-old BALB/c mice were randomly divided into three groups: control group (PBS group), model group (BLM group), and tocilizumab group (TCZ group). The mRNA expression of VIMENTIN, TIMP1, and COL1A1 was measured by qPCR. Western blot was used to detect the protein expression of α-SMA, TGF-β, and COL1A1 in skin tissues. The expression of CD38⁺ macrophages in the BLM-induced fibrosis mouse model was verified by flow cytometry and immunofluorescence.

Results

In comparison to the PBS control group, mice in the BLM group showed skin fibrosis, edema, thickness, and collagen deposition. The percentage of macrophages in the skin, peripheral blood, and spleen was significantly increased in the BLM group, and the percentage of CD38⁺ macrophages increased in the skin and peripheral blood but decreased in the spleen. After co-cultured with macrophages, L929 fibroblasts differentiated into myofibroblasts, with increased mRNA expression of COL1A1, COL3A, TGF-β, and Fibronectin. Furthermore, after being stimulated by LPS, RAW264.7 cells showed increased expression of IL-6 and CD38. The mRNA levels of COL1A1, COL1A2, COL3A, TGF-β, and Fibronectin in L929 fibroblasts were markedly increased when co-cultured with LPS-stimulated RAW264.7 cells. Tocilizumab treatment reduced dermal thickness and collagen deposition induced by BLM. Furthermore, the percentage of total macrophages and CD38⁺ macrophages in the skin and peripheral blood significantly decreased after tocilizumab treatment.

Conclusion

This study revealed that tocilizumab improved skin fibrosis in the SSc mice model, which was mediated by inhibiting skin and peripheral CD38⁺ macrophages.

背景：皮肤和肺纤维化是系统性硬皮病（SSc）的主要临床症状，目前尚无有效的治疗药物。Tocilizumab被认为可以改善纤维化症状，但Tocilizumab对真皮纤维化的影响尚未被探索。本研究旨在探讨tocilizumab通过抑制CD38+巨噬细胞在博莱霉素诱导的SSc小鼠模型中对皮肤纤维化的治疗作用。方法：将8周龄BALB/c小鼠随机分为3组：对照组（PBS组）、模型组（BLM组）、托珠单抗组（TCZ组）。采用qPCR检测VIMENTIN、TIMP1、COL1A1 mRNA的表达。Western blot检测皮肤组织中α-SMA、TGF-β、COL1A1蛋白的表达。用流式细胞术和免疫荧光技术验证CD38+巨噬细胞在blm诱导纤维化小鼠模型中的表达。结果：与PBS对照组比较，BLM组小鼠出现皮肤纤维化、水肿、增厚、胶原沉积。BLM组皮肤、外周血和脾脏中巨噬细胞百分比显著升高，皮肤和外周血中CD38+巨噬细胞百分比升高，脾脏中CD38+巨噬细胞百分比降低。与巨噬细胞共培养后，L929成纤维细胞分化为肌成纤维细胞，COL1A1、COL3A、TGF-β、纤维连接蛋白mRNA表达增加。此外，经LPS刺激后，RAW264.7细胞IL-6和CD38的表达增加。与lps刺激的RAW264.7细胞共培养后，L929成纤维细胞COL1A1、COL1A2、COL3A、TGF-β和纤维连接蛋白mRNA水平显著升高。托珠单抗治疗可减少BLM诱导的真皮厚度和胶原沉积。此外，托珠单抗治疗后，皮肤和外周血中总巨噬细胞和CD38+巨噬细胞的百分比显著降低。结论：本研究揭示tocilizumab改善SSc小鼠模型皮肤纤维化，其机制是通过抑制皮肤和外周血CD38+巨噬细胞介导。

{"title":"The effect of tocilizumab treatment for skin fibrosis by inhibiting CD38+ macrophages in systemic sclerosis","authors":"Hongzhen Chen , Dapeng Yang , Yirui Shi , Haolin Wu , Huiming Zhu , Tingting Jiang , Shu Liu , Dandan Wang","doi":"10.1016/j.cellimm.2024.104914","DOIUrl":"10.1016/j.cellimm.2024.104914","url":null,"abstract":"<div><h3>Background</h3><div>Dermal and pulmonary fibrosis are the main clinical symptoms of systemic scleroderma (SSc), for which there are no effective therapeutic agents. Tocilizumab is thought to improve the symptoms of fibrosis, but the effect of tocilizumab on dermal fibrosis has not been explored. This study aims to investigate the therapeutic effect of tocilizumab on skin fibrosis by inhibiting CD38<sup>+</sup> macrophages in the bleomycin-induced SSc mice model.</div></div><div><h3>Methods</h3><div>The 8-week-old BALB/c mice were randomly divided into three groups: control group (PBS group), model group (BLM group), and tocilizumab group (TCZ group). The mRNA expression of VIMENTIN, TIMP1, and COL1A1 was measured by qPCR. Western blot was used to detect the protein expression of α-SMA, TGF-β, and COL1A1 in skin tissues. The expression of CD38<sup>+</sup> macrophages in the BLM-induced fibrosis mouse model was verified by flow cytometry and immunofluorescence.</div></div><div><h3>Results</h3><div>In comparison to the PBS control group, mice in the BLM group showed skin fibrosis, edema, thickness, and collagen deposition. The percentage of macrophages in the skin, peripheral blood, and spleen was significantly increased in the BLM group, and the percentage of CD38<sup>+</sup> macrophages increased in the skin and peripheral blood but decreased in the spleen. After co-cultured with macrophages, L929 fibroblasts differentiated into myofibroblasts, with increased mRNA expression of COL1A1, COL3A, TGF-β, and Fibronectin. Furthermore, after being stimulated by LPS, RAW264.7 cells showed increased expression of IL-6 and CD38. The mRNA levels of COL1A1, COL1A2, COL3A, TGF-β, and Fibronectin in L929 fibroblasts were markedly increased when co-cultured with LPS-stimulated RAW264.7 cells. Tocilizumab treatment reduced dermal thickness and collagen deposition induced by BLM. Furthermore, the percentage of total macrophages and CD38<sup>+</sup> macrophages in the skin and peripheral blood significantly decreased after tocilizumab treatment.</div></div><div><h3>Conclusion</h3><div>This study revealed that tocilizumab improved skin fibrosis in the SSc mice model, which was mediated by inhibiting skin and peripheral CD38<sup>+</sup> macrophages.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104914"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Augmented IFNγ producing ILC1 and IL 17 producing ILC3 in pemphigus vulgaris: Plausible therapeutic target 寻常型天疱疮中IFNγ增强产生ILC1和IL 17产生ILC3：可能的治疗靶点。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104910

Vishakha Hooda , Sujay Khandpur , Alpana Sharma

Innate Lymphoid cells (ILCs) are innate counterparts of helper T cells. Although low in number, they have proven to play major roles in many autoimmune diseases. In Pemphigus Vulgaris (PV), the gaps in the knowledge of functional role of ILCs remain. To bridge the gap, our study investigated the phenotype along with the functional determinants of ILCs involved in PV immunopathogenesis. Our data suggested augmentation in overall ILC population in circulation of PV patients. Specifically, ILC1 and ILC3 subtypes were significantly increased in peripheral circulation of PV patients compared to healthy controls. We observed no changes in ILC2 population. mRNAs from ILC enriched population showed significant upregulation in transcription factors- ID2, T bet and RORγt and a downregulation in GATA3 and RORα. The mRNA levels of ILC related cytokines- IFNγ and IL17 were significantly upregulated while no change was observed in the levels of IL13, IL 22, AHR. The levels of autoantibodies against desmoglein (Dsg) 3 which is the characteristic of PV pathogenesis were also checked in the serum which confirmed significant upregulation in PV patients. The levels of proinflammatory- IFNγ, IL 17 and IL 15 were elevated and anti-inflammatory cytokines- IL10 was downregulated in the serum of PV patients. The results of this study offer insights into the functional attributes of ILCs and related cytokines, potentially contributing to the development of future therapeutic interventions.

先天淋巴样细胞（ILCs）是辅助T细胞的先天对应物。虽然数量很少，但它们已被证明在许多自身免疫性疾病中发挥重要作用。在寻常型天疱疮（PV）中，ILCs的功能作用知识仍然存在空白。为了弥补这一空白，我们的研究调查了表型以及参与PV免疫发病的ILCs的功能决定因素。我们的数据表明PV患者血液循环中的ILC总体增加。具体而言，与健康对照组相比，PV患者外周循环中的ILC1和ILC3亚型显著增加。我们观察到ILC2人群没有变化。ILC富集群体mrna中转录因子- ID2、tbet和RORγt显著上调，GATA3和RORα显著下调。ILC相关细胞因子IFNγ和IL17 mRNA水平显著上调，IL13、IL 22、AHR mRNA水平未见变化。血清中抗粘粒蛋白（Dsg） 3的自身抗体水平也被检测，这是PV发病机制的特征，证实了PV患者的显著上调。PV患者血清促炎因子- IFNγ、IL 17、IL 15水平升高，抗炎因子- IL10水平下调。这项研究的结果提供了对ilc和相关细胞因子的功能属性的见解，可能有助于未来治疗干预措施的发展。

{"title":"Augmented IFNγ producing ILC1 and IL 17 producing ILC3 in pemphigus vulgaris: Plausible therapeutic target","authors":"Vishakha Hooda , Sujay Khandpur , Alpana Sharma","doi":"10.1016/j.cellimm.2024.104910","DOIUrl":"10.1016/j.cellimm.2024.104910","url":null,"abstract":"<div><div>Innate Lymphoid cells (ILCs) are innate counterparts of helper T cells. Although low in number, they have proven to play major roles in many autoimmune diseases. In Pemphigus Vulgaris (PV), the gaps in the knowledge of functional role of ILCs remain. To bridge the gap, our study investigated the phenotype along with the functional determinants of ILCs involved in PV immunopathogenesis. Our data suggested augmentation in overall ILC population in circulation of PV patients. Specifically, ILC1 and ILC3 subtypes were significantly increased in peripheral circulation of PV patients compared to healthy controls. We observed no changes in ILC2 population. mRNAs from ILC enriched population showed significant upregulation in transcription factors- ID2, T bet and RORγt and a downregulation in GATA3 and RORα. The mRNA levels of ILC related cytokines- IFNγ and IL17 were significantly upregulated while no change was observed in the levels of IL13, IL 22, AHR. The levels of autoantibodies against desmoglein (Dsg) 3 which is the characteristic of PV pathogenesis were also checked in the serum which confirmed significant upregulation in PV patients. The levels of proinflammatory- IFNγ, IL 17 and IL 15 were elevated and anti-inflammatory cytokines- IL10 was downregulated in the serum of PV patients. The results of this study offer insights into the functional attributes of ILCs and related cytokines, potentially contributing to the development of future therapeutic interventions.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104910"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The double-edged sword role of natural Killer cells in Parkinson's disease.

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-01-23 DOI: 10.1016/j.cellimm.2025.104928

Delbar Daneshjou, Seyed Masood Nabavi, Parisa Shams, Pooya Faranoush, Mehri Salari, Marzieh Ebrahimi

Neurological disorders are the leading cause of disability worldwide, with Parkinson's disease (PD) emerging as a rapidly growing neurological condition on a global scale. Although treatments exist to alleviate symptoms and maintain patients' quality of life, PD remains incurable. According to some recent studies, natural killer (NK) cells may play a role in clearing alpha-synuclein aggregates, which are the main component of Lewy bodies that cause neuronal degeneration in Parkinson's disease. NK cells may also have an adverse impact on this condition by modulating inflammation and antigen-presenting cell function. Modifying NK cells derived from diverse sources, such as umbilical cord blood, presents a promising avenue for immunotherapy in PD patients, particularly during the early stages of the condition. Consequently, further research is essential to elucidate the mechanisms by which NK cells operate in Parkinson's patients and to assess their viability as potential biomarkers or therapeutic targets.

引用次数: 0

Effect of high-fat diet on IgA⁺ cells and BAFF/APRIL in small intestinal villous lamina propria of mice.

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-01-21 DOI: 10.1016/j.cellimm.2024.104911

Yuta Sakamoto, Masatoshi Niwa, Ken Muramatsu, Satoshi Shimo

Obesity exacerbates susceptibility to infectious diseases. We investigated the effects of a high-fat diet (HFD) on intestinal immunity, particularly immunoglobulin (Ig)A-producing cells, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) localization. Mice (4- to 20-weeks old) were fed HFD or standard chow diet, and their jejunum and ileum were fixed using the in vivo cryotechnique. Immunohistochemistry was performed for IgA, BAFF, and APRIL. In the HFD group, IgA⁺, IgA⁺CD22⁺ (p < 0.001), and IgA⁺CD138^- (p = 0.007) cell counts were diminished in the middle sections of the lamina propria of jejunal villi, and BAFF levels were significantly reduced in jejunal villi. The HFD effects on IgA⁺ cell distribution seem to be confined to jejunal villi, hinting at localized vulnerabilities in intestinal immunity during obesity. Moreover, in the HFD group, IgA⁺ B-cell counts were reduced in the middle jejunum, indicating inhibition of the IgA⁺ B-cells through a T-cell-independent pathway.

{"title":"Effect of high-fat diet on IgA<sup>+</sup> cells and BAFF/APRIL in small intestinal villous lamina propria of mice.","authors":"Yuta Sakamoto, Masatoshi Niwa, Ken Muramatsu, Satoshi Shimo","doi":"10.1016/j.cellimm.2024.104911","DOIUrl":"https://doi.org/10.1016/j.cellimm.2024.104911","url":null,"abstract":"<p><p>Obesity exacerbates susceptibility to infectious diseases. We investigated the effects of a high-fat diet (HFD) on intestinal immunity, particularly immunoglobulin (Ig)A-producing cells, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) localization. Mice (4- to 20-weeks old) were fed HFD or standard chow diet, and their jejunum and ileum were fixed using the in vivo cryotechnique. Immunohistochemistry was performed for IgA, BAFF, and APRIL. In the HFD group, IgA<sup>+</sup>, IgA<sup>+</sup>CD22<sup>+</sup> (p < 0.001), and IgA<sup>+</sup>CD138<sup>-</sup> (p = 0.007) cell counts were diminished in the middle sections of the lamina propria of jejunal villi, and BAFF levels were significantly reduced in jejunal villi. The HFD effects on IgA<sup>+</sup> cell distribution seem to be confined to jejunal villi, hinting at localized vulnerabilities in intestinal immunity during obesity. Moreover, in the HFD group, IgA<sup>+</sup> B-cell counts were reduced in the middle jejunum, indicating inhibition of the IgA<sup>+</sup> B-cells through a T-cell-independent pathway.</p>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409-410 ","pages":"104911"},"PeriodicalIF":3.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

IL-17 family members exert an autocrine pro-inflammatory loop in CF respiratory epithelial cells ex vivo. IL-17家族成员体外在CF呼吸上皮细胞中发挥自分泌促炎回路。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-01-17 DOI: 10.1016/j.cellimm.2025.104926

Caterina Allegretta, Enza Montemitro, Fabiana Ciciriello, Maria Teresa Altieri, Giuseppe Sabbioni, Giulia Breveglieri, Monica Borgatti, Giulio Cabrini, Onofrio Laselva

Background: Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease.

Methods: We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells.

Results: Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17 A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17 A and F were induced to release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13).

Conclusion: These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.

背景：囊性纤维化（pwCF）患者的肺部以慢性炎症和铜绿假单胞菌感染为特征。在pwCF患者的痰中观察到高水平的il - 17a和F，白细胞介素-17（IL-17）家族（A-to-F）被认为在CF肺部疾病中起关键作用。方法：采用RT-qPCR方法检测铜绿假单胞菌PAO1菌株或pwCF临床外产物（EXO）感染CF支气管上皮（CFBE）细胞后IL-17受体（IL-17R） mRNA水平。采用RT-qPCR检测CF原代鼻上皮（HNE）培养细胞IL-17 mRNA的表达，ELISA和Bioplex检测细胞因子的释放。结果：15 pwCF中分离的PAO1或EXO感染CFBE细胞后，除IL-17RD外，其余IL-17R mRNA表达均显著升高。从相应供体分离的EXO感染HNE细胞后，除IL-17D和IL-17RD外，所有IL-17细胞因子和受体的mRNA水平均显著升高，细胞因子il - 17a、IL-17B、IL-17C、IL-17E和IL-17F的释放均显著升高。暴露于il - 17a和F的HNE被诱导释放促炎细胞因子（IL-1β, IL-6, TNF-α），中性粒细胞趋化因子（IL-8, G-CSF）和已知参与氯化物和碳酸氢盐分泌的细胞因子，以及粘蛋白上调（IL-4, IL-13）。结论：这些结果提示IL-17家族成员在呼吸上皮细胞中广泛表达，可在CF气道中发挥自分泌炎症扩增环的作用。这些使用患者源性培养的体外研究强调了IL-17家族成员在CF肺免疫应答中的相关作用。

{"title":"IL-17 family members exert an autocrine pro-inflammatory loop in CF respiratory epithelial cells ex vivo.","authors":"Caterina Allegretta, Enza Montemitro, Fabiana Ciciriello, Maria Teresa Altieri, Giuseppe Sabbioni, Giulia Breveglieri, Monica Borgatti, Giulio Cabrini, Onofrio Laselva","doi":"10.1016/j.cellimm.2025.104926","DOIUrl":"https://doi.org/10.1016/j.cellimm.2025.104926","url":null,"abstract":"<p><strong>Background: </strong>Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease.</p><p><strong>Methods: </strong>We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells.</p><p><strong>Results: </strong>Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17 A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17 A and F were induced to release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13).</p><p><strong>Conclusion: </strong>These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.</p>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409-410 ","pages":"104926"},"PeriodicalIF":3.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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