Macrophage-Kruppel-Like Transcription Factor 6 Signaling Promotes Experimental Atherogenesis

Area of Science:

• Immunology
• Cardiovascular Biology
• Molecular Biology

Background:

• Macrophages are central to atherosclerosis, influencing plaque initiation, growth, and rupture.
• These innate immune cells orchestrate atherogenesis through inflammation, matrix degradation, and phagocytosis.
• Understanding macrophage regulation is crucial for developing atherosclerosis therapies.

Purpose of the Study:

• To investigate the role of Kruppel-like transcription factor 6 (KLF6) in macrophage-driven inflammation and atherosclerosis.
• To determine the molecular mechanisms by which KLF6 influences proinflammatory gene expression in macrophages.
• To assess the in vivo impact of KLF6 deficiency on atherosclerotic plaque development.

Main Methods:

• Utilized myeloid-specific KLF6 deficiency in Apoe-null mice fed a high-fat/high-cholesterol diet.
• Performed integrated transcriptomics and Gene Set Enrichment Analysis (GSEA) on macrophages.
• Investigated molecular pathways involving KLF6, interferon regulatory factor 1 (IRF1), and tumor necrosis factor (TNF) signaling.

Main Results:

• KLF6 deficiency significantly attenuated proinflammatory gene expression in macrophages.
• Myeloid KLF6 deficiency reduced atherosclerotic lesion formation and macrophage accumulation in vivo.
• KLF6 deficiency curtailed TNF-induced gene targets, interferon responses, and inflammatory signaling pathways.
• KLF6 was found to promote IRF1 signaling, enhancing TNF-induced proinflammatory gene expression.

Conclusions:

• KLF6 plays a pro-atherogenic role by promoting inflammatory gene expression in macrophages.
• Targeting KLF6 may represent a novel therapeutic strategy for atherosclerosis.
• KLF6's regulation of inflammatory signaling pathways is critical in atherogenesis.