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.
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
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引用次数: 0
Abstract
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.
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