N⁶-Adenosine Methylation of Socs1 mRNA Is Required to Sustain the Negative Feedback Control of Macrophage Activation

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Bacterial infections trigger cytokine storms, requiring resolution for host survival.
• Macrophage activation is critical in host defense but must be tightly regulated.

Purpose of the Study:

• To investigate the role of METTL14 in myeloid cells during bacterial infection.
• To elucidate the molecular mechanisms by which METTL14 regulates macrophage responses.

Main Methods:

• Mice with myeloid-specific METTL14 ablation were used.
• Macrophage activation, cytokine production, and signaling pathways (TLR4/NF-κB) were analyzed.
• Messenger RNA (mRNA) methylation, protein binding (YTHDF1), and gene induction (SOCS1) were assessed.

Main Results:

• METTL14 ablation in myeloid cells led to exacerbated macrophage responses and increased mortality in mice.
• METTL14 deficiency reduced m6A methylation of Socs1 mRNA, impairing SOCS1 induction and leading to TLR4/NF-κB overactivation.
• Restoring SOCS1 expression rescued the hyper-inflammatory phenotype.
• FTO expression mimicked METTL14-depleted phenotypes, suggesting its role in regulating SOCS1 mRNA stability.

Conclusions:

• METTL14-mediated m6A methylation of Socs1 is essential for negative feedback control of macrophage activation during bacterial infection.
• This pathway is critical for maintaining immune homeostasis and preventing excessive inflammation.