Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury

Area of Science:

• Immunology
• Gastroenterology
• Pathophysiology

Background:

• Intestinal ischemia reperfusion (IR) injury is a severe condition with high mortality.
• Complement activation is implicated in IR injury, with emerging evidence suggesting sex-based differences.
• The precise mechanisms of sex-dependent complement initiation in intestinal IR remain unclear.

Purpose of the Study:

• To investigate sex-specific differences in complement activation pathways during intestinal IR.
• To determine the roles of C1q, MBL, and properdin in sex-dependent intestinal IR injury.

Main Methods:

• Intestinal IR was induced in male and female wildtype, C1q-deficient, MBL-deficient, and properdin-deficient mice.
• Analysis included assessment of intestinal injury, C3b and C5a production, and ex vivo secretions.
• Complement mRNA and protein expression were evaluated in wildtype mice.

Main Results:

• Male mice deficient in C1q, MBL, or properdin showed reduced IR injury compared to wildtype males.
• Only female MBL-deficient mice exhibited significantly less injury than wildtype females.
• Wildtype, C1q-deficient, and P-deficient female mice experienced less injury than their male counterparts.
• Males showed increased C1q and MBL deposition, while females showed elevated MBL deposition post-IR.
• Females produced less C5a in MBL-deficient and P-deficient mice.

Conclusions:

• Complement activation plays a critical role in intestinal IR injury in a sex-dependent manner.
• Males rely on both the classical (C1q) and lectin (MBL) complement pathways.
• Females predominantly depend on the lectin (MBL) pathway for complement activation in intestinal IR.