Methyltransferase like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, has been implicated in various biological and pathological processes including immune responses. However, the functions and mechanisms of METTL3 in pathogenic T helper (Th)17 cells are poorly understood. Here we found significantly decreased METTL3 expression along with reduced m6A levels in eyeballs and T cells of experimental autoimmune uveitis (EAU). Overexpression of METTL3 ameliorated the development of EAU and suppressed pathogenic Th17 cell responses in vivo and in vitro. Mechanistically, METTL3 promoted the expression of absent, small, or homeotic-like 1 (ASH1L) via enhancing its stability in a YT521-B homology domain containing 2 (YTHDC2)-dependent manner, which further decreased the expression of IL-17 and IL-23 receptor (IL-23R), resulting in reduced pathogenic Th17 responses. Together, our data reveal a pivotal role of METTL3 in regulating pathogenic Th17 responses, which may contribute to human uveitis therapy.
Keyphrases
- poor prognosis
- single cell
- juvenile idiopathic arthritis
- binding protein
- ankylosing spondylitis
- immune response
- multiple sclerosis
- cell therapy
- endothelial cells
- induced apoptosis
- cell proliferation
- stem cells
- rheumatoid arthritis
- regulatory t cells
- municipal solid waste
- genome wide
- cell cycle arrest
- long non coding rna
- inflammatory response
- systemic lupus erythematosus
- risk assessment
- oxidative stress
- big data
- cell death
- artificial intelligence
- pi k akt
- endoplasmic reticulum stress
- replacement therapy