MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via...

Area of Science:

• Neuroscience
• Epigenetics
• Molecular Biology

Background:

• Gene transcription and translation dysfunctions in nociceptive pathways are crucial in chronic pain development.
• Circular RNAs (circRNAs) are novel regulators of gene expression, but their role in chronic pain is largely unknown.

Purpose of the Study:

• To investigate the role of circRNAs, specifically circRNA-Filip1l, in the mechanisms of chronic inflammation pain.
• To elucidate the regulatory pathway involving miRNA-1224, Argonaute-2 (Ago2), and circRNA-Filip1l in nociception.

Main Methods:

• Utilized a mouse model of chronic inflammation pain induced by complete Freund's adjuvant.
• Measured circRNA-Filip1l and miRNA-1224 expression in spinal neurons.
• Employed knockdown and overexpression techniques for circRNA-Filip1l, miRNA-1224, and Ago2.
• Identified Ubr5 as a target gene of circRNA-Filip1l.

Main Results:

• Complete Freund's adjuvant induced significant upregulation of circRNA-Filip1l in spinal neurons, which correlated with increased nociceptive behaviors.
• circRNA-Filip1l expression was negatively regulated by miRNA-1224 in an Ago2-dependent manner; decreased miRNA-1224 led to increased circRNA-Filip1l.
• Overexpression of circRNA-Filip1l mimicked pain behaviors, while its knockdown prevented pain behaviors induced by miRNA-1224 knockdown or Ago2 overexpression.
• circRNA-Filip1l regulated nociception by targeting the ubiquitin protein ligase E3 component n-recognin 5 (Ubr5).

Conclusions:

• Spinal circRNA-Filip1l plays a critical role in the development and maintenance of chronic inflammation pain.
• A novel epigenetic mechanism involving miRNA-1224-mediated, Ago2-dependent regulation of circRNA-Filip1l controls nociception via the Ubr5 pathway.
• This study reveals a new interaction between miRNAs and circRNAs in the context of chronic pain.