Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: The inflammasome complex has recently emerged as a driver of organ damage in systemic lupus erythematosus (SLE). This complex, via its enzymatic subunit caspase-1, is responsible for the cleavage and activation of the inflammatory cytokines IL-1β and IL-18. While type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation has not been assessed in this disease. In this study, we examine type I IFNs as regulators of inflammasome activation, and identify interferon regulatory factor-1 (IRF-1) as the critical intersection between the two pathways.
Methods : All patients and controls gave written, informed consent and were treated according to the declaration of Helsinki. SLE patients fulfilled
Results: Expression of inflammasome (caspase-1, NLRP3, ASC, IL-1β) and interferon-regulated genes (IFI44, MX1, IRF-1) was tightly and significantly correlated in lupus, but not control, monocytes. Indeed, lupus monocytes exhibited increased expression and enhanced activation of the inflammasome by ATP when compared to control monocytes. Importantly, inflammasome activity was increased in control and SLE monocytes with prolonged, but not brief, exposure to IFNα. IFNα treatment resulted in robust upregulation of caspase-1 and IRF-1, a known transcription factor of caspase-1. Reduction of IRF-1 expression via siRNA blocked caspase-1 upregulation after treatment with IFNα. Importantly, hyperactivity of the inflammasome in lupus monocytes was significantly reduced after knock-down of IRF-1.
Conclusion: Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF-1-dependent manner. IRF-1 inhibition may serve as a novel target for treatment of SLE-associated inflammation and organ damage.
To cite this abstract in AMA style:Liu J, Kahlenberg JM. Interferon Regulatory Factor 1 Is the Key Driver of Inflammasome Activity in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/interferon-regulatory-factor-1-is-the-key-driver-of-inflammasome-activity-in-systemic-lupus-erythematosus/. Accessed December 5, 2020.
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