Background/Purpose: Systemic Lupus Erythematosus (SLE) is a prototypical autoimmune disease defined by autoantibody production, immune dysregulation, and end-organ damage. Our laboratory previously showed that MyD88, a signaling component of IL-1 and Toll-like receptors (TLR) 7 and 9, is a central mediator of SLE pathogenesis. Genetic studies have clearly implicated TLR7 and TLR9 in regulating disease. However, though evidence in humans and mouse models suggests a pathogenic role for IL-1, this has not been directly tested. Data from our laboratory suggest that dermatitis in murine SLE is MyD88 dependent but TLR7/9 independent, differing from systemic manifestations of the disease.

Methods:  Tissue homogenates from diseased MRL.Fas^lpr (MRL/lpr) mice and non-diseased tissues were evaluated by qPCR. MRL/lpr mice were crossed with IL1R1^-/- mice and evaluated initially as an F2 intercross cohort, a validated and rapid method for screening for genetic control of autoimmunity in the context of an autoimmune-predisposing genetic background. Subsequently, the Il1r1 loss of function allele was backcrossed for 7 generations and then made homozygous; this cohort was analyzed for disease pathology at 16 weeks for females and 19 weeks for males. We evaluated proteinuria, renal histology, dermatitis, ANA, and immune cell activation via flow cytometry.

Results:  IL-1β mRNA levels were increased in kidneys of MRL/lpr mice with proteinuria nearly 5-fold compared to non-diseased young MRL/lpr mice (p=0.05); and in inflamed skin, IL-1β mRNA levels were elevated nearly 50 fold compared to controls (p<0.005). There was no significant difference in proteinuria, glomerulonephritis, ANA production, or spleen size. However, dermatitis was significantly reduced in the IL-1R1 deficient F2 Fas^lpr mice (p<0.008) compared to littermate controls. This finding was recapitulated in the backcrossed cohort wherein we observed decreased rates of dermatitis in the IL1R1^-/- mice compared with littermate MRL/lpr controls.

Conclusion:  This study supports the theory that there are differential mechanisms for tissue specific manifestations of systemic autoimmune diseases, specifically, while TLR7/9 regulates systemic manifestations of SLE upstream of MyD88, IL-1 regulates dermatitis. Overall these findings provide evidence that IL-1 signaling is a significant contributor to autoimmune dermatitis in the MRL model and may be a potential target for treating cutaneous lupus manifestations.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-il-1-signaling-ameliorates-dermatitis-in-a-murine-model-of-systemic-lupus-erythematosus/