Background/Purpose: Premature cardiovascular disease (CVD) represents a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE).  We recently proposed that type I interferon (IFN) modulation of the inflammasome and resultant IL-18 production contribute to dysfunction of endothelial progenitor cells (EPC) in SLE patients. This phenomenon may promote an imbalance of vascular damage and repair and increase CV risk. Thus, we hypothesize that activation of the inflammasome may play an important role in CVD development in SLE.  In order to determine the role of caspase-1, the central enzyme of the inflammasome and activator of IL-18 and IL-1beta, in the enhanced risk of CVD in SLE, we utilized the type-I IFN dependent, pristane-induced model of murine lupus in wild type and caspase-1 deficient mice.

Methods: 8 week old C57Bl/6 (WT) mice or C57Bl/6 caspase-1 -/- (KO) mice were injected intraperitoneally with 0.5 ml pristane or 0.5 ml PBS, and euthanized 6 months post injection.  Aortic rings were assessed for relaxation following acetylcholine (Ach) exposure as a measure of endothelial function.  Bone marrow EPCs were quantified by FACs and their capacity to differentiate into mature endothelial cells (ECs) was assessed by fluorescent microscopy. Lupus phenotype was also quantified.

Results: Aortas isolated from pristane-exposed wild type mice had dysfunctional relaxation, similar to what has been described in other lupus models and in SLE patients. In contrast, endothelial relaxation in caspase-1 KO mice exposed to pristane was significantly improved when compared to that observed in pristane treated wild-type mice.  This suggests that caspase-1 is required for SLE mediated endothelial dysfunction.  Bone marrow EPC numbers trended toward a reduction in numbers in pristane exposed wild type but not caspase-1 knockout mice.  Additionally, the capacity of these cells to differentiate into mature ECs was significantly preserved in pristane treated caspase-1 KO mice compared to pristane treated WT mice.  This indicates that caspase-1 contributes to lupus-induced aberrant EPC function in vivo.  Lupus phenotype is currently being compared between the two groups.

Conclusion:  In pristane-induced lupus, the absence of caspase-1 is protective against endothelial dysfunction and aberrant EPC function. This observation implicates inflammasome modulation by type I IFNs as an important contributor to cardiovascular damage in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/caspase-1-modulates-endothelial-dysfunction-and-vascular-repair-in-murine-lupus/