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METTL3 regulates LPS-induced inflammatory response via the NOD1 signaling pathway

Yongjie Cai1, Ruiqing Yu1, Yiping Kong1

  • 1Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.

Cellular Signalling
|February 17, 2022
PubMed

Insights

Methyltransferase-like 3 (METTL3) depletion enhances the inflammatory response in macrophages by stabilizing NOD1 and RIPK2 mRNA. This process involves the NOD-like receptor signaling pathway and increases pro-inflammatory cytokines.

Area of Science:

  • Immunology
  • Epigenetics
  • Molecular Biology

Background:

  • N6-methyladenosine (m6A) is a key mRNA modification impacting biological processes.
  • Methyltransferase-like 3 (METTL3) is essential for m6A modification, but its role in immune response is debated.
  • METTL3 expression and m6A levels decrease in LPS-stimulated macrophages.

Purpose of the Study:

  • To investigate the role of METTL3 in the inflammatory response of macrophages.
  • To elucidate the molecular mechanisms by which METTL3 influences immune signaling pathways.

Main Methods:

  • Macrophage stimulation with LPS and METTL3 knockdown.
  • Measurement of m6A levels and pro-inflammatory cytokine expression (TNF-α, IL-6, NO).
  • RNA sequencing, pathway analysis (NOD-like receptor signaling), and validation using pathway inhibitors and silencing of m6A-binding proteins (YTHDF1, YTHDF2).

Main Results:

  • METTL3 knockdown significantly increased pro-inflammatory cytokines and NO production.
  • Upregulated genes were enriched in inflammation-related pathways, particularly the NOD1 pathway.
  • METTL3 depletion stabilized NOD1 and RIPK2 mRNA by inhibiting YTHDF1/YTHDF2-mediated degradation, leading to enhanced inflammation.

Conclusions:

  • METTL3 depletion promotes LPS-induced inflammatory responses in macrophages.
  • The mechanism involves the upregulation of the NOD1 pathway due to increased NOD1 and RIPK2 mRNA stability.
  • METTL3 acts as a negative regulator of the inflammatory response in macrophages via m6A modification of NOD1 and RIPK2.
Keywords:
InflammationMETTL3MacrophageNOD1 signaling pathwaymRNA degradation

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