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Pharmacological modulation and genetic deletion of REV-ERBα and REV-ERBβ regulates dendritic cell development
Mohammed Amir1, Sean Campbell1, Theodore M Kamenecka2
1Department of Immunology and Microbiology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
Abstract:
The nuclear receptors REV-ERBα and REV-ERBβ have been demonstrated to play key roles in the regulation of numerous physiological functions, such as metabolism and the circadian rhythm. Recent studies have established the REV-ERBs' roles in immunity, including macrophage and T cell responses. In contrast, their roles in dendritic cells have not been well defined. Dendritic cells are potent antigen presenting cells, connecting microbial sensing and innate immunity to adaptive immune responses. We demonstrate that both REV-ERBα and REV-ERBβ expression is upregulated during the course of bone marrow derived dendritic cell (BMDC) differentiation. BMDCs from REV-ERBα and REV-ERBβ deficient mice showed enhanced expression of maturation markers like CD86, MHCII, and proinflammatory cytokines. Conversely, treatment of BMDCs with a REV-ERB-specific agonist, SR9009, inhibited the expression of maturation markers and proinflammatory cytokines. Our study suggests the REV-ERBs act as negative regulators of dendritic cell development and activation. These results indicate that pharmacological modulation of REV-ERB activity could be an attractive strategy to modulate DC activation status and for DC-based therapies.
Insights
Nuclear receptors REV-ERBα and REV-ERBβ negatively regulate dendritic cell (DC) development and activation. Their deficiency enhances DC maturation, while agonists like SR9009 inhibit it, suggesting therapeutic potential.
Area of Science:
- Immunology
- Cell Biology
- Molecular Endocrinology
Background:
- Nuclear receptors REV-ERBα and REV-ERBβ regulate metabolism and circadian rhythms.
- REV-ERBs are implicated in macrophage and T cell immunity.
- The role of REV-ERBs in dendritic cells (DCs) remains largely undefined.
Purpose of the Study:
- To investigate the role of REV-ERBα and REV-ERBβ in dendritic cell differentiation and activation.
- To determine if REV-ERBs act as regulators of DC maturation and function.
Main Methods:
- Analysis of REV-ERBα and REV-ERBβ expression during bone marrow-derived dendritic cell (BMDC) differentiation.
- Assessment of DC maturation markers (CD86, MHCII) and cytokine production in REV-ERB deficient BMDCs.
- Pharmacological inhibition of REV-ERB activity using the agonist SR9009 in BMDCs.
Main Results:
- REV-ERBα and REV-ERBβ expression increased during BMDC differentiation.
- BMDCs deficient in REV-ERBs exhibited enhanced expression of maturation markers and pro-inflammatory cytokines.
- SR9009 treatment suppressed DC maturation markers and pro-inflammatory cytokine production.
Conclusions:
- REV-ERBα and REV-ERBβ function as negative regulators of dendritic cell development and activation.
- Pharmacological targeting of REV-ERBs offers a potential strategy for modulating DC activity in therapies.
