Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis

Area of Science:

• Immunology
• Molecular Biology
• Pathogenesis of Sepsis

Background:

• Toll-like receptor 4 (TLR4) activation by bacterial endotoxins is key in sepsis pathogenesis.
• The precise mechanism of TLR4 activation in macrophages remains incompletely understood.

Purpose of the Study:

• To elucidate the role of post-translational modifications in TLR4 signaling during sepsis.
• To investigate the involvement of lysine acetyltransferase CBP in TLR4 activation and macrophage polarization.

Main Methods:

• Investigated the recruitment of CBP to the TLR4 signalosome upon lipopolysaccharide (LPS) stimulation.
• Assessed the impact of TLR4-TIR domain acetylation on NF-κB and IRF3 signaling pathways.
• Analyzed M1 macrophage polarization markers in response to TLR4 activation.
• Examined TLR4-TIR acetylation levels and M1 markers in monocytes from sepsis patients.
• Evaluated the effects of inhibiting CBP and HDAC1 on sepsis progression.

Main Results:

• LPS stimulation recruits lysine acetyltransferase CBP to the TLR4 signalosome, increasing TIR domain acetylation.
• Acetylation of TLR4-TIR domains enhances NF-κB signaling, promoting M1 macrophage polarization.
• Elevated TLR4-TIR acetylation and M1 markers were observed in CD16+ monocytes from sepsis patients.
• Pharmacological inhibition of CBP or HDAC1 differentially impacts sepsis progression.

Conclusions:

• TLR4-TIR domain acetylation is a critical regulator of immune responses in sepsis.
• Reversible acetylation of TLR4 signalosomes represents a potential therapeutic target for managing M1 macrophage polarization in sepsis.