Retinoic acid induced cytokines are selectively modulated by liver X receptor activation in zebrafish
Oscar E Diaz1, Shuangjia Xue2, Xinxin Luo3
1Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176, Stockholm, Sweden; Center of Molecular Medicine, 17176, Stockholm, Sweden.
Abstract:
Nuclear receptors (NRs) rapidly activate/repress gene expression to detour immune responses and allow tissue adaptation to constant environmental changes. However, the effect of combined NRs in the immune system is often unclear due to the lack of reliable experimental models that recapitulate the complex interaction between NRs in vivo. Here, we used the zebrafish to investigate the immunological outcome of combining the activation of retinoic acid receptor (RAR), liver X receptor (LXR) and the cytoplasmic sensor aryl hydrocarbon receptor (AHR). Although simultaneous activation did not affect the expression of respective bona-fide target genes, RAR-induced il17a/f3 was antagonized by LXR and AHR, whereas il22 was antagonized by AHR but not LXR. In addition, RA decreased il10 expression, which was further decreased by LXR activation. Thus, using combinatorial NR activation in zebrafish larvae, we show that LXR antagonizes the expression of selected RA-induced cytokines and provide a strategy to tailor the cytokine milieu.
Insights
Combining nuclear receptors (NRs) like retinoic acid receptor (RAR) and liver X receptor (LXR) in zebrafish revealed LXR antagonizes RAR-induced cytokines, offering a strategy to modulate immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Endocrinology
Background:
- Nuclear receptors (NRs) regulate gene expression crucial for immune responses and tissue adaptation.
- Understanding the combined effects of NRs on immunity is challenging due to limited in vivo models.
- NRs like retinoic acid receptor (RAR), liver X receptor (LXR), and aryl hydrocarbon receptor (AHR) play significant roles in immune modulation.
Purpose of the Study:
- To investigate the immunological consequences of simultaneously activating RAR, LXR, and AHR in vivo.
- To explore the interactions between these NRs in controlling cytokine expression.
- To establish a zebrafish model for studying combinatorial NR effects on the immune system.
Main Methods:
- Utilized zebrafish larvae as a model organism for in vivo experiments.
- Simultaneously activated retinoic acid receptor (RAR), liver X receptor (LXR), and aryl hydrocarbon receptor (AHR).
- Analyzed the expression of specific cytokine genes, including il17a/f3, il22, and il10.
Main Results:
- Simultaneous NR activation did not alter the expression of their direct target genes.
- LXR and AHR antagonized RAR-induced il17a/f3 expression.
- AHR, but not LXR, antagonized il22 expression.
- Retinoic acid (RA) decreased il10 expression, an effect further enhanced by LXR activation.
Conclusions:
- Combinatorial activation of NRs in zebrafish larvae demonstrates specific antagonistic interactions between LXR and RAR.
- LXR activation antagonizes selected RA-induced cytokines, providing insights into immune regulation.
- This study presents a strategy for tailoring the cytokine milieu through combinatorial NR activation.
