Pparα knockout in mice increases the Th17 development by facilitating the IKKα/RORγt and IKKα/Foxp3 complexes.
Ping WeiWei KouJuan FuZuojia ChenFan PanPublished in: Communications biology (2023)
The helper CD4 + T cell-type 17 (Th17) cells and regulatory CD4 + T cells (Tregs) are balanced through numerous molecular regulators, particularly metabolic factors, and their alteration causes immune dysregulation. Herein, we report that peroxisome proliferator of activated receptor-alpha (Pparα), a lipid metabolism regulator, suppresses Th17 differentiation. We demonstrated that Pparα ablation improves Th17 and pro-Th17 factor HIF-1α by enhancing the expression and nuclear localization of NFκB-activator IκB kinase-alpha (IKKα). Unexpectedly, we found that IKKα directly interacts with RORγt and enhances the expression of Il17a gene. Meanwhile, IKKα also interacts with Foxp3, leading to the post-translational regulation of Foxp3 by elevating its proteasomal degradation, and influencing Th17 development. Pparα deficiency leads to enhanced Th17 development in vivo and is associated with enhanced pathology in a murine experimental autoimmune encephalomyelitis (EAE) model. Overall, our data indicate that Pparα may serve as a potential therapeutic target for autoimmune and inflammatory diseases.
Keyphrases
- regulatory t cells
- insulin resistance
- binding protein
- poor prognosis
- fatty acid
- signaling pathway
- transcription factor
- induced apoptosis
- multiple sclerosis
- high fat diet induced
- nuclear factor
- machine learning
- gene expression
- lps induced
- endoplasmic reticulum stress
- cell death
- skeletal muscle
- cell cycle arrest
- deep learning
- single molecule
- electronic health record
- climate change
- inflammatory response
- protein kinase
- atrial fibrillation
- human health
- catheter ablation
- genome wide identification