4-1BBL Suppresses Anti-Inflammatory Responses by Regulating Metabolic Reprogramming of Macrophages

Area of Science:

• Immunology
• Cell Biology
• Metabolic Regulation

Background:

• Macrophage polarization is crucial for immune responses, involving integration of signaling and metabolism.
• 4-1BB ligand (4-1BBL) is known for pro-inflammatory roles, but its anti-inflammatory function is unclear.

Purpose of the Study:

• To investigate the role of 4-1BBL in regulating anti-inflammatory macrophage polarization.
• To elucidate the molecular mechanisms by which 4-1BBL influences macrophage inflammatory and metabolic states.

Main Methods:

• Genetic deletion and pharmacological inhibition of 4-1BBL in mouse macrophages.
• Analysis of cytokine expression, JAK1/STAT6 phosphorylation, and metabolic gene signatures.
• Transcriptomic analysis and studies in human monocytes.

Main Results:

• 4-1BBL deficiency enhanced anti-inflammatory cytokine and marker expression.
• 4-1BBL inhibited IL-4R signaling by restraining JAK1 and STAT6 phosphorylation.
• 4-1BBL deficiency promoted oxidative phosphorylation and fatty acid oxidation in anti-inflammatory macrophages.
• 4-1BBL inhibition augmented anti-inflammatory responses in human monocytes.

Conclusions:

• 4-1BBL acts as a negative regulator of anti-inflammatory macrophage polarization.
• 4-1BBL integrates inflammatory signaling with metabolic reprogramming.
• Targeting 4-1BBL may be a therapeutic strategy for promoting inflammation resolution.