Cyclin J-CDK complexes limit innate immune responses by reducing proinflammatory changes in macrophage metabolism

Area of Science:

• Immunology
• Cell Biology
• Metabolic Regulation

Background:

• Toll-like receptor (TLR) stimulation activates macrophages, increasing glycolysis and mitochondrial reactive oxygen species (ROS) production, which are crucial for inflammation.
• Dysregulated metabolic reprogramming in macrophages contributes to various inflammatory diseases.

Purpose of the Study:

• To investigate the role of cyclin J, a TLR-inducible protein, in regulating macrophage inflammatory responses.
• To elucidate the molecular mechanisms by which cyclin J controls glycolysis and mitochondrial function.

Main Methods:

• Studied cyclin J's interaction with cyclin-dependent kinases (CDKs).
• Analyzed the phosphorylation of CDK substrates like FoxK1 and Drp1.
• Assessed the impact of cyclin J on gene transcription, ROS production, and mitochondrial morphology.
• Evaluated cyclin J's effects on tumor growth, LPS-induced shock, and bacterial infection in mice.

Main Results:

• Cyclin J reduced cytokine production by controlling glycolysis and mitochondrial function in macrophages.
• Cyclin J-CDK signaling phosphorylated FoxK1, decreasing glycolytic gene transcription and Hif-1α activation.
• Cyclin J-dependent phosphorylation of Drp1 led to mitochondrial fragmentation and reduced ROS production.
• In vivo, cyclin J limited tumor xenograft growth and protected against LPS shock, but increased susceptibility to bacterial infection.

Conclusions:

• Cyclin J-CDK signaling opposes metabolic reprogramming in macrophages, thereby promoting antitumor immunity and inflammation resolution.
• Targeting cyclin J-CDK pathways may offer therapeutic strategies for inflammatory diseases and cancer.