Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-κB...

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• p21-activated kinases (PAKs) regulate cell motility, but their role in macrophage differentiation and polarization is unclear.
• Macrophage polarization is crucial for immune responses and inflammatory diseases.

Purpose of the Study:

• To investigate the role of PAK1 in macrophage polarization and inflammatory responses.
• To elucidate the regulatory mechanism of PAK1 in M1 macrophage polarization.

Main Methods:

• Overexpression and knockout studies in human and murine macrophages.
• Analysis of the EZH2/let-7c/PAK1 signaling axis.
• Assessment of lipopolysaccharide (LPS)-induced endotoxin shock models.
• Pharmacological and genetic inhibition strategies.

Main Results:

• Inflammatory stimuli induced PAK1 overexpression in macrophages.
• Elevated PAK1 promoted M1 polarization and LPS-induced endotoxin shock.
• EZH2 upregulation led to let-7c loss, increasing PAK1 and M1 phenotype.
• The EZH2/let-7c/PAK1 axis activates NIK-IKK-NF-κB signaling.
• Inhibition of this axis or PAK1 deletion conferred resistance to endotoxin shock.

Conclusions:

• PAK1 is a critical regulator of inflammatory macrophage M1 polarization.
• The EZH2/let-7c/PAK1 pathway controls macrophage inflammatory responses.
• Targeting this axis offers a potential therapeutic strategy for inflammatory diseases.