Macrophage-produced IL-12p70 mediates hemorrhage-induced damage in a complement-dependent manner

Area of Science:

• Immunology
• Gastroenterology
• Pathology

Background:

• Hemorrhage and hemorrhagic shock lead to intestinal damage and inflammation.
• Innate immune responses, including complement activation and neutrophil infiltration, contribute to this pathology.

Purpose of the Study:

• To investigate the interplay between complement activation and innate immunity during hemorrhage.
• To assess the therapeutic potential of inhibiting the alternative complement pathway in mitigating intestinal injury.

Main Methods:

• Mice were subjected to hemorrhage and treated with CR2-fH, an inhibitor of the alternative complement pathway.
• Intestinal damage and inflammation markers were evaluated 2 hours post-hemorrhage.
• Macrophage depletion using clodronate-liposomes was employed to determine their role.

Main Results:

• CR2-fH treatment significantly reduced hemorrhage-induced midjejunal damage and inflammation in wild-type mice.
• This reduction was associated with decreased mucosal damage, macrophage infiltration, and lower levels of leukotriene B4, IL-12p40, and TNF-α.
• Depletion of macrophages or blockade of IL-12p70 also attenuated intestinal damage, underscoring their critical involvement.

Conclusions:

• Complement activation and subsequent macrophage infiltration, leading to IL-12p70 production, are critical mediators of hemorrhage-induced midjejunal damage and inflammation.
• Targeting the alternative complement pathway with CR2-fH shows promise in treating intestinal injury following hemorrhagic shock.