AMPK/HuR-Driven IL-20 Post-Transcriptional Regulation in Psoriatic Skin

Abstract

IL-20 is involved in the development of skin psoriasis. The molecular mechanisms underlying IL-20 overexpression in psoriatic epidermis remain to be elucidated. We showed that IL-20 was primarily upregulated in psoriatic skin at the post-transcriptional level. The RNA-binding protein HuR relocalized to the cytoplasm of keratinocytes (KCs) of psoriatic patients, suggesting that it stabilizes numerous transcripts, as observed in the human KC cell lines used to assess IL-20 mRNA. We characterized epidermal HuR RNA targets in psoriatic skin using ribonucleoprotein immunoprecipitation analyzed via high-throughput sequencing. Numerous transcripts that are upregulated in psoriasis were targeted by HuR, supporting the participation of HuR in pathogenic processes such as morphological changes, innate and adaptive immune responses, and metabolic inflammatory responses. Finally, we identified the metabolic sensor AMP-activated protein kinase (AMPK) as being responsible for HuR cytoplasmic relocalization because its activity was severely impaired in human psoriatic epidermis, and in vivo drug-mediated AMPK inhibition in mouse epidermis promoted HuR cytoplasmic localization, IL-20 overproduction, acanthosis, and hyperkeratosis. These results provide insights into the molecular links between metabolism and post-transcriptional networks during chronic inflammation.