Kruppel-like Factor 6 Promotes Macrophage-mediated Inflammation by Suppressing B Cell Leukemia/Lymphoma 6 Expression

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Macrophages are key innate immune cells involved in inflammation following injury or infection.
• Tight regulation of macrophage pro-inflammatory gene expression is crucial to prevent host tissue damage.

Purpose of the Study:

• To identify novel regulators of macrophage inflammatory gene expression and function.
• To elucidate the role of the Kruppel-like transcription factor 6 (KLF6)-B cell leukemia/lymphoma 6 (BCL6) signaling axis in macrophage biology.

Main Methods:

• Utilized complementary gain- and loss-of-function studies in macrophages.
• Investigated KLF6's role in macrophage motility ex vivo and in vivo.
• Assessed the impact of myeloid-specific KLF6 deficiency on inflammation.
• Examined molecular mechanisms involving PR domain-containing 1 with ZNF domain (PRDM1) and BCL6 expression.
• Evaluated the effects of BCL6 inhibition in KLF6-deficient macrophages.

Main Results:

• KLF6 is essential for macrophage motility.
• Myeloid-specific deficiency of KLF6 significantly attenuates macrophage pro-inflammatory gene expression, recruitment, and inflammation progression.
• KLF6 suppresses BCL6 expression by increasing PRDM1 levels.
• Inhibition of BCL6 in KLF6-deficient macrophages reversed the attenuation of pro-inflammatory responses and motility.

Conclusions:

• The KLF6-BCL6 signaling axis is a novel regulator of macrophage inflammatory gene expression and function.
• KLF6 represses BCL6 to enhance macrophage inflammatory gene expression and function, highlighting a new mechanism for controlling inflammation.