Activation of the alternative complement pathway modulates inflammation in thoracic aortic aneurysm/dissection

Area of Science:

• Vascular Biology
• Immunology
• Genetics

Background:

• Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening condition involving aortic medial degeneration.
• The complement C3a-C3aR axis in smooth muscle cells is implicated in TAAD, but the initiating complement pathway remains unclear.

Purpose of the Study:

• To identify the specific complement pathway involved in TAAD pathogenesis.
• To elucidate the mechanisms by which aortic wall inflammation is initiated in TAAD.

Main Methods:

• Measured plasma levels of complement anaphylatoxins (C3a, C4a, C5a) in patients with TAAD.
• Utilized a TAAD mouse model with gene knockouts (Cfb, C4) and receptor antagonists.
• Administered exogenous complement factor B (CFB) to Cfb knockout mice.
• Investigated the role of CFB in FBN1^C1041G/+ Marfan syndrome mice.

Main Results:

• Elevated C3a and C5a levels were observed in patients with TAAD, with higher levels in acute cases.
• The alternative complement pathway and CFB were found to be critical in TAAD development in mice.
• Blocking complement receptors reduced inflammatory cell recruitment to the aortic wall.
• Exogenous CFB exacerbated TAAD onset and rupture, while CFB knockout reduced TAAD incidence in Marfan mice.

Conclusions:

• The alternative complement pathway promotes TAAD by recruiting infiltrating inflammatory cells.
• Targeting the alternative complement pathway presents a potential therapeutic strategy for preventing TAAD.