Targeting Myeloid FoxO1 Ameliorates Sepsis-induced Intestinal Injury by Modulating Tim4⁺ Macrophage Glycolysis.

Area of Science:

• Immunology
• Molecular Biology
• Gastroenterology

Background:

• Sepsis-induced intestinal injury is a severe complication linked to macrophage dysfunction.
• The role of the transcription factor Forkhead Box O1 (FoxO1) in this process is not well understood.

Purpose of the Study:

• To investigate the function of myeloid FoxO1 in sepsis-induced intestinal injury.
• To identify FoxO1 as a potential therapeutic target for this condition.

Main Methods:

• Utilized myeloid-specific FoxO1 conditional knockout (FoxO1^M-KO) mice to study sepsis.
• Analyzed macrophage populations, intestinal barrier function, oxidative stress, and inflammatory markers.
• Investigated molecular mechanisms involving FoxO1, Sin3a, Tim4, and MAP4K4 signaling.
• Evaluated the therapeutic potential of Huashi Baidu formula (HSBD).

Main Results:

• FoxO1 expression was upregulated in intestinal macrophages during sepsis.
• FoxO1 deletion in myeloid cells alleviated intestinal injury, improved barrier function, and reduced oxidative stress and systemic inflammation.
• FoxO1 deficiency increased Tim4⁺ resident macrophages, suppressed glycolysis via MAP4K4 signaling, and exerted anti-inflammatory effects.
• Adoptive transfer experiments confirmed the critical role of FoxO1-regulated Tim4⁺ macrophages.
• HSBD treatment inhibited FoxO1 and ameliorated septic intestinal injury.

Conclusions:

• Myeloid FoxO1 plays a crucial immunomodulatory role in sepsis-induced intestinal injury.
• Targeting FoxO1, particularly within Tim4⁺ macrophages, represents a novel therapeutic strategy for sepsis.
• Traditional Chinese medicine HSBD demonstrates potential in mitigating this condition by modulating FoxO1.