Antonia Becker, Karoline Röhrich, Amanda Leske, Ulrike Heinicke, Tilo Knape, Aimo Kannt, Verena Trümper, Kai Sohn, Annett Wilken-Schmitz, Holger Neb, Elisabeth H Adam, Volker Laux, Michael J Parnham, Valerie Onasch, Andreas Weigert, Kai Zacharowski, Andreas von Knethen
{"title":"鉴定 CRTH2 是 T 细胞中新的 PPARγ 靶基因，建议将 CRTH2 依赖性 Th2 细胞转化作为 COVID-19 感染的治疗概念。","authors":"Antonia Becker, Karoline Röhrich, Amanda Leske, Ulrike Heinicke, Tilo Knape, Aimo Kannt, Verena Trümper, Kai Sohn, Annett Wilken-Schmitz, Holger Neb, Elisabeth H Adam, Volker Laux, Michael J Parnham, Valerie Onasch, Andreas Weigert, Kai Zacharowski, Andreas von Knethen","doi":"10.2147/ITT.S463601","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>COVID-19 is a serious viral infection, which is often associated with a lethal outcome. Therefore, understanding mechanisms, which affect the immune response during SARS-CoV2 infection, are important.</p><p><strong>Methods: </strong>To address this, we determined the number of T cells in peripheral blood derived from intensive care COVID-19 patients. Based on our previous studies, evaluating PPARγ-dependent T cell apoptosis in sepsis patients, we monitored PPARγ expression. We performed a next generation sequencing approach to identify putative PPARγ-target genes in Jurkat T cells and used a PPARγ transactivation assay in HEK293T cells. Finally, we translated these data to primary T cells derived from healthy donors.</p><p><strong>Results: </strong>A significantly reduced count of total CD3<sup>+</sup> T lymphocytes and the CD4<sup>+</sup> and CD8<sup>+</sup> subpopulations was observed. Also, the numbers of anti-inflammatory, resolutive T<sub>h</sub>2 cells and FoxP3-positive regulatory T cells (T<sub>reg</sub>) were decreased. We observed an augmented PPARγ expression in CD4<sup>+</sup> T cells of intensive care COVID-19 patients. Adapted from a next generation sequencing approach in Jurkat T cells, we found the chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) as one gene regulated by PPARγ in T cells. This T<sub>h</sub>2 marker is a receptor for prostaglandin D and its metabolic degradation product 15-deoxy-∆12,14-prostaglandin J<sub>2</sub> (15d-PGJ<sub>2</sub>), an established endogenous PPARγ agonist. In line, we observed an increased PPARγ transactivation in response to 15d-PGJ<sub>2</sub> treatment in HEK293T cells overexpressing CRTH2. Translating these data to primary T cells, we found that T<sub>h</sub>2 differentiation was associated with an increased expression of CRTH2. Interestingly, these CRTH2<sup>+</sup> T cells were prone to apoptosis.</p><p><strong>Conclusion: </strong>These mechanistic data suggest an involvement of PPARγ in T<sub>h</sub>2 differentiation and T cell depletion in COVID-19 patients.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"595-616"},"PeriodicalIF":6.2000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539866/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identification of CRTH2 as a New PPARγ-Target Gene in T Cells Suggested CRTH2 Dependent Conversion of T<sub>h</sub>2 Cells as Therapeutic Concept in COVID-19 Infection.\",\"authors\":\"Antonia Becker, Karoline Röhrich, Amanda Leske, Ulrike Heinicke, Tilo Knape, Aimo Kannt, Verena Trümper, Kai Sohn, Annett Wilken-Schmitz, Holger Neb, Elisabeth H Adam, Volker Laux, Michael J Parnham, Valerie Onasch, Andreas Weigert, Kai Zacharowski, Andreas von Knethen\",\"doi\":\"10.2147/ITT.S463601\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>COVID-19 is a serious viral infection, which is often associated with a lethal outcome. Therefore, understanding mechanisms, which affect the immune response during SARS-CoV2 infection, are important.</p><p><strong>Methods: </strong>To address this, we determined the number of T cells in peripheral blood derived from intensive care COVID-19 patients. Based on our previous studies, evaluating PPARγ-dependent T cell apoptosis in sepsis patients, we monitored PPARγ expression. We performed a next generation sequencing approach to identify putative PPARγ-target genes in Jurkat T cells and used a PPARγ transactivation assay in HEK293T cells. Finally, we translated these data to primary T cells derived from healthy donors.</p><p><strong>Results: </strong>A significantly reduced count of total CD3<sup>+</sup> T lymphocytes and the CD4<sup>+</sup> and CD8<sup>+</sup> subpopulations was observed. Also, the numbers of anti-inflammatory, resolutive T<sub>h</sub>2 cells and FoxP3-positive regulatory T cells (T<sub>reg</sub>) were decreased. We observed an augmented PPARγ expression in CD4<sup>+</sup> T cells of intensive care COVID-19 patients. Adapted from a next generation sequencing approach in Jurkat T cells, we found the chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) as one gene regulated by PPARγ in T cells. This T<sub>h</sub>2 marker is a receptor for prostaglandin D and its metabolic degradation product 15-deoxy-∆12,14-prostaglandin J<sub>2</sub> (15d-PGJ<sub>2</sub>), an established endogenous PPARγ agonist. In line, we observed an increased PPARγ transactivation in response to 15d-PGJ<sub>2</sub> treatment in HEK293T cells overexpressing CRTH2. Translating these data to primary T cells, we found that T<sub>h</sub>2 differentiation was associated with an increased expression of CRTH2. Interestingly, these CRTH2<sup>+</sup> T cells were prone to apoptosis.</p><p><strong>Conclusion: </strong>These mechanistic data suggest an involvement of PPARγ in T<sub>h</sub>2 differentiation and T cell depletion in COVID-19 patients.</p>\",\"PeriodicalId\":30986,\"journal\":{\"name\":\"ImmunoTargets and Therapy\",\"volume\":\"13 \",\"pages\":\"595-616\"},\"PeriodicalIF\":6.2000,\"publicationDate\":\"2024-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539866/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ImmunoTargets and Therapy\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2147/ITT.S463601\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ImmunoTargets and Therapy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2147/ITT.S463601","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：COVID-19 是一种严重的病毒感染：COVID-19是一种严重的病毒感染，通常会导致死亡。因此，了解影响 SARS-CoV2 感染期间免疫反应的机制非常重要：为此，我们测定了重症监护 COVID-19 患者外周血中 T 细胞的数量。根据我们以前对败血症患者中 PPARγ 依赖性 T 细胞凋亡的评估研究，我们监测了 PPARγ 的表达。我们采用新一代测序方法鉴定了 Jurkat T 细胞中 PPARγ 的潜在靶基因，并在 HEK293T 细胞中使用了 PPARγ 转录激活试验。最后，我们将这些数据转化为来自健康供体的原代 T 细胞：结果：我们观察到 CD3+ T 淋巴细胞总数、CD4+ 和 CD8+ 亚群数量明显减少。此外，抗炎、溶解性 Th2 细胞和 FoxP3 阳性调节性 T 细胞（Treg）的数量也减少了。我们在重症监护 COVID-19 患者的 CD4+ T 细胞中观察到 PPARγ 表达增强。通过对 Jurkat T 细胞进行新一代测序，我们发现 T 辅助 2 型细胞上表达的趋化受体同源分子（CRTH2）是 T 细胞中受 PPARγ 调节的基因之一。这种 Th2 标志物是前列腺素 D 及其代谢降解产物 15-脱氧-Δ12,14-前列腺素 J2（15d-PGJ2）的受体，而前列腺素 J2 是一种公认的内源性 PPARγ 激动剂。同样，我们在过表达 CRTH2 的 HEK293T 细胞中观察到，PPARγ 在 15d-PGJ2 处理下的转录活化增加。将这些数据转化到原代 T 细胞中，我们发现 Th2 分化与 CRTH2 的表达增加有关。有趣的是，这些 CRTH2+ T 细胞容易凋亡：这些机理数据表明 PPARγ 参与了 COVID-19 患者的 Th2 分化和 T 细胞耗竭。
Identification of CRTH2 as a New PPARγ-Target Gene in T Cells Suggested CRTH2 Dependent Conversion of Th2 Cells as Therapeutic Concept in COVID-19 Infection.
Background: COVID-19 is a serious viral infection, which is often associated with a lethal outcome. Therefore, understanding mechanisms, which affect the immune response during SARS-CoV2 infection, are important.
Methods: To address this, we determined the number of T cells in peripheral blood derived from intensive care COVID-19 patients. Based on our previous studies, evaluating PPARγ-dependent T cell apoptosis in sepsis patients, we monitored PPARγ expression. We performed a next generation sequencing approach to identify putative PPARγ-target genes in Jurkat T cells and used a PPARγ transactivation assay in HEK293T cells. Finally, we translated these data to primary T cells derived from healthy donors.
Results: A significantly reduced count of total CD3+ T lymphocytes and the CD4+ and CD8+ subpopulations was observed. Also, the numbers of anti-inflammatory, resolutive Th2 cells and FoxP3-positive regulatory T cells (Treg) were decreased. We observed an augmented PPARγ expression in CD4+ T cells of intensive care COVID-19 patients. Adapted from a next generation sequencing approach in Jurkat T cells, we found the chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) as one gene regulated by PPARγ in T cells. This Th2 marker is a receptor for prostaglandin D and its metabolic degradation product 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), an established endogenous PPARγ agonist. In line, we observed an increased PPARγ transactivation in response to 15d-PGJ2 treatment in HEK293T cells overexpressing CRTH2. Translating these data to primary T cells, we found that Th2 differentiation was associated with an increased expression of CRTH2. Interestingly, these CRTH2+ T cells were prone to apoptosis.
Conclusion: These mechanistic data suggest an involvement of PPARγ in Th2 differentiation and T cell depletion in COVID-19 patients.
期刊介绍：
Immuno Targets and Therapy is an international, peer-reviewed open access journal focusing on the immunological basis of diseases, potential targets for immune based therapy and treatment protocols employed to improve patient management. Basic immunology and physiology of the immune system in health, and disease will be also covered.In addition, the journal will focus on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
