RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Spliceosome dysfunction and aberrant RNA splicing are implicated in unresolved inflammation and immunopathogenesis.
• Rheumatoid arthritis (RA) pathogenesis involves complex molecular mechanisms, including altered gene expression and immune cell dysregulation.

Purpose of the Study:

• To investigate the role of mRNA splicing and the spliceosome in rheumatoid arthritis (RA).
• To identify key factors involved in RA pathogenesis and explore potential therapeutic targets.

Main Methods:

• Multiomics analyses of macrophages from RBM25-deficient mice.
• Investigated the interaction of RBM25 with ATP citrate lyase (Acly) pre-mRNA.
• Assessed the impact of Acly isoforms on macrophage metabolism and inflammation.
• Utilized mouse models of arthritis and inflammation.

Main Results:

• Decreased RNA binding motif protein 25 (RBM25) expression exacerbates RA by increasing proinflammatory mediators and hyperinflammation in macrophages.
• RBM25 deficiency alters histone modifications and hypoxia-inducible factor-1α (HIF-1α) activity, enhancing proinflammatory gene transcription.
• RBM25 mediates alternative splicing of Acly, producing Acly Long (Acly L) and Acly Short (Acly S) isoforms.
• Acly S isoform accumulation, driven by RBM25 deficiency, enhances glycolysis and acetyl-CoA production, promoting macrophage overactivation and inflammatory injury.
• Macrophage-specific RBM25 deletion induced inflammaging and arthritis, which were ameliorated by Acly inhibition.

Conclusions:

• The RBM25-Acly splicing axis is a critical regulator of macrophage function in RA and aging-associated inflammation.
• Targeting the RBM25-Acly pathway offers a potential therapeutic strategy for autoimmune arthritis and related inflammatory conditions.