Negative regulation of Th17 cell development and function by the REV-ERBs

Autor: Laura A Solt, Mohammed Amir, Sweena M. Chaudhari, Ran Wang, Sean Campbell
Rok vydání: 2017
Předmět:
Zdroj: The Journal of Immunology. 198:127.15-127.15
ISSN: 1550-6606
0022-1767
Popis: A significant amount of work has identified key factors that drive Th17 cell development, including the nuclear receptors (NRs) RORα and RORγ. However, cell-intrinsic mechanisms that negatively regulate Th17 cell development and inflammation have received less attention. Two other members of the NR superfamily, the REV-ERBs (REV-ERBα and REV-ERBβ), are often co-expressed in the same tissues as the RORs, bind the same DNA response elements, and co-regulate their shared target genes. The REV-ERBs have well described roles in the regulation of the circadian rhythm and metabolism, but their roles in immune cell function are poorly understood. Therefore, we hypothesize that the REV-ERBs are key negative regulators of Th17 cell development and function. We we aim to understand the role of the REV-ERBs in Th17 cell development as well as determine whether targeting these NRs is a viable therapeutic option for the treatment of Th17-mediated autoimmune diseases. Our results indicate that the REV-ERBs are differentially expressed during Th17 cell development. Overexpression and pharmacological modulation of REV-ERB activity suppresses Th17 cell development whereas genetic deletion of the REV-ERBs perturbs Th17 cell development in vitro and induces autoimmunity in vivo. Using REV-ERB-specific small molecules that we have developed, we have found that pharmacological modulation of REV-ERB activity suppresses Th17 cell development in vitro and development of autoimmunity in vivo. Collectively, our data suggest that the REV-ERBs are key negative regulators of Th17 cell development and function and represent a novel therapeutic target for the treatment of Th17-mediated autoimmune diseases. Funding support – NIH (R01AI116885-01A1)
Databáze: OpenAIRE
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