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METTL14-m6A-FOXO3a axis regulates autophagy and inflammation in ankylosing spondylitis

Yuting Chen1, Ye Wu1, Lanlan Fang1

  • 1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.

Clinical Immunology (Orlando, Fla.)
|November 7, 2023
PubMed

Insights

Methyltransferase-like 14 (METTL14) is downregulated in ankylosing spondylitis (AS), impairing autophagy and increasing inflammation. Restoring METTL14 alleviates AS symptoms by upregulating Forkhead box O3a (FOXO3a).

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • Ankylosing spondylitis (AS) pathogenesis involves complex molecular mechanisms.
  • The role of N6-methyladenosine (m6A) modification in AS is not well understood.
  • Understanding epigenetic regulators like METTL14 is crucial for AS research.

Purpose of the Study:

  • To investigate the role of m6A modification and METTL14 in T cells of AS patients.
  • To elucidate the molecular mechanism by which METTL14 influences autophagy and inflammation in AS.
  • To explore METTL14 as a potential therapeutic target for AS.

Main Methods:

  • Analysis of m6A modification levels in T cells from AS patients.
  • Assessment of methyltransferase-like 14 (METTL14) expression and its correlation with AS.
  • Investigation of METTL14's regulatory effect on Forkhead box O3a (FOXO3a) expression and autophagy.
  • Experimental manipulation of METTL14 levels to observe effects on autophagy and inflammation.

Main Results:

  • m6A modification and METTL14 expression were significantly decreased in T cells of AS patients.
  • Downregulation of METTL14 led to reduced FOXO3a expression, impaired autophagic flux, and aggravated inflammation.
  • Overexpression of METTL14 restored FOXO3a levels, activated autophagy, and alleviated inflammation.
  • METTL14 was found to directly target FOXO3a mRNA, regulating its expression and stability in an m6A-dependent manner.

Conclusions:

  • METTL14 plays a critical role in regulating autophagy and inflammation in AS through the m6A-dependent regulation of FOXO3a.
  • The findings reveal a novel epigenetic mechanism contributing to AS pathogenesis.
  • METTL14-FOXO3a pathway represents a potential therapeutic target for developing novel treatment strategies for AS.
Keywords:
Ankylosing spondylitisAutophagyFOXO3aInflammationMETTL14m6A

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