Background/Purpose: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune syndrome associated with organ damage and an elevated risk of cardiovascular disease (CVD) resulting from activation of both innate and adaptive immune pathways.  Recently, increased activation of the inflammasome machinery in SLE has been described. This study explores if caspase-1, the central enzyme of the inflammasome, plays a role in the development of SLE and its associated vascular dysfunction, using the pristane model of lupus. 

Methods: Eight-week old wild-type or caspase-1 -/- mice were exposed to PBS or pristane via intraperitoneal injection.  Six months post injection, mice were euthanized and the development of a lupus phenotype and vascular dysfunction was assessed. 

Results: Both wild-type and caspase-1 KO mice develop a vigorous inflammatory response to pristane; however, cell death following pristane exposure is decreased in caspase-1 -/- mice.  While wild-type mice exposed to pristane develop autoantibodies and a strong type I IFN response, mice lacking caspase-1 are significantly protected from these features, including pristane-induced vascular dysfunction.  Further, the development of immune-complex glomerulonephritis, prominent after pristane exposure in wild-type mice, is significantly abrogated in caspase-1 -/- mice. 

Conclusion: These results indicate that caspase-1 is an essential component in the development of lupus and its associated vascular dysfunction following exposure to pristane.  Importantly, caspase-1 may modulate autoantigen generation through regulation of cell death.  Thus, caspase-1 may play an important role in the cross-talk between environmental exposures and autoimmunity development, providing a novel pathway for therapeutic targeting.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-essential-role-for-caspase-1-in-the-induction-of-murine-lupus-and-its-associated-vascular-damage/