ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Biology

Background:

• Macrophage activation by pathogen-associated molecular patterns (PAMPs) like LPS and LTA induces a proinflammatory state and metabolic shifts.
• The interplay between metabolic reprogramming and gene expression in activated macrophages is not fully understood.
• ATP citrate lyase (ACLY) is a key enzyme in generating acetyl-CoA for cellular biosynthesis and inflammatory responses.

Purpose of the Study:

• To investigate the role of ACLY in macrophage activation and inflammatory gene expression.
• To elucidate the mechanism by which ACLY influences the NF-κB signaling pathway.
• To identify potential feedback loops involving ACLY and inflammatory gene regulation.

Main Methods:

• Immunocytochemistry and cytosol-nucleus fractionation to assess ACLY localization.
• Protein immunoprecipitation to study protein interactions.
• Analysis of gene expression in human peripheral blood mononuclear cell (PBMC)-derived macrophages.

Main Results:

• ACLY undergoes rapid nuclear translocation upon macrophage stimulation.
• Nuclear ACLY acetylates NF-κB, leading to its full activation.
• Sepsis, in its hyperinflammatory phase, shows increased ACLY-mediated NF-κB acetylation.
• The ACLY/NF-κB pathway upregulates proinflammatory genes, including SLC25A1 and ACLY itself.

Conclusions:

• ACLY plays a critical role in NF-κB activation and the subsequent induction of a proinflammatory phenotype in macrophages.
• A positive feedback loop involving ACLY, NF-κB, and the SLC25A1 gene sustains macrophage inflammation.
• Targeting the ACLY/NF-κB axis may offer therapeutic strategies for hyperinflammatory conditions like sepsis.