Lactate-driven macrophage polarization in the inflammatory microenvironment alleviates intestinal inflammation

Area of Science:

• Immunology
• Metabolism
• Cell Biology

Background:

• Lactate was traditionally viewed as a glucose metabolism byproduct.
• Emerging evidence highlights lactate's distinct biological roles, including anti-inflammatory signaling.
• Previous in vitro studies indicated lactate's potential to shift macrophages from pro-inflammatory to anti-inflammatory phenotypes.

Purpose of the Study:

• To investigate the in vivo anti-inflammatory effects of lactate.
• To determine if lactate can alleviate inflammation in a mouse model.
• To explore the mechanisms underlying lactate's immunomodulatory actions.

Main Methods:

• RAW 264.7 macrophages were stimulated with LPS and treated with lactate to assess phenotypic changes and inflammatory mediator expression.
• Inflammatory factors in cell-free supernatants were analyzed.
• A mouse model of DSS-induced colitis was established and treated with lactate, with colonic tissue injury assessed histopathologically.

Main Results:

• In vitro, lactate promoted M2 macrophage polarization and reduced TLR4-mediated NF-κB signaling and inflammatory factors.
• In vivo, lactate treatment in DSS-induced colitis reduced inflammation, organ damage, and TLR4/NF-κB activation.
• Lactate increased anti-inflammatory factors, promoted intestinal barrier repair, and ameliorated colitis severity.

Conclusions:

• Lactate inhibits the TLR/NF-κB pathway and pro-inflammatory factor production via macrophage polarization.
• Lactate promotes intestinal mucosal barrier repair and protects against inflammatory damage.
• Lactate represents a safe and promising therapeutic agent for inflammation through immunometabolism regulation.