The alternative complement pathway propagates inflammation and injury in murine ischemic stroke

Area of Science:

• Immunology
• Neuroscience
• Vascular Biology

Background:

• Complement system activation is implicated in ischemic stroke pathogenesis.
• The specific roles of the alternative and terminal complement pathways in ischemic stroke remain unclear.

Purpose of the Study:

• To investigate the role of the alternative complement pathway in cerebral ischemia-reperfusion injury.
• To determine the involvement of the terminal complement pathway in ischemic stroke.

Main Methods:

• Utilized a mouse model of middle cerebral artery occlusion and reperfusion.
• Examined outcomes in mice deficient in alternative pathway protein factor B, or treated with CR2-fH inhibitor.
• Assessed outcomes in mice deficient in classical and lectin pathways (C1q/MBL deficient) and C6-deficient mice.

Main Results:

• Factor B deficiency or CR2-fH treatment improved neurologic function and reduced infarct size, demyelination, P-selectin expression, neutrophil infiltration, and microthrombi.
• Mice deficient in classical/lectin pathways were protected, with no C3d deposition.
• C6 deficiency did not affect outcomes, indicating the membrane attack complex is not involved.

Conclusions:

• The alternative complement pathway propagates cerebral injury via cascade amplification, but is not sufficient alone to initiate activation.
• The terminal complement pathway, specifically the membrane attack complex, does not mediate injury in this ischemic stroke model.
• Targeting the alternative complement pathway offers a promising therapeutic strategy for ischemic stroke, with sustained benefits observed in the subacute phase.