Date: Monday, October 22, 2018
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which 70% of patients experience disfiguring skin inflammation (grouped under the rubric of cutaneous lupus erythematosus (CLE)). Studies have revealed that interferons (IFNs) are important mediators for SLE and CLE, but the mechanisms by which IFNs lead to disease are still poorly understood. We and others have previously identified increased type I IFN expression in non-lesional SLE keratinocytes, but whether alterations in response to IFNs also contribute to disease is unknown. We thus aimed to investigate IFN responses in SLE vs. control keratinocytes and to identify mechanisms by which differential regulation may occur.
Methods: Age and gender-matched control (n=7) and SLE (n=7) keratinocytes were isolated from non-lesional, non-sun exposed 6mm punch skin biopsies from the upper thigh and used at passage 3. All patients gave written, informed consent and were treated according to the Declaration of Helsinki. These keratinocytes were treated with or without 5 ng/mL of IFNα, IFNβ, IFNκ, and IFNγ for 6 hours followed by RNA isolation and RNA-sequencing. In-depth analysis of the interferon response was conducted. PITX1 expression in normal and CLE lesional skin was evaluated by immunohistochemistry. Knockdown of PITX1 was used to examine IFN gene expression in the absence of PITX1.
Results: A significant hypersensitive response to IFNs was identified in lupus keratinocytes including genes (IFIH1, STAT1, and IRF7) encompassed in SLE susceptibility loci. In particular, 273 genes in SLE keratinocytes demonstrated a higher effect size (p=5.8×10-32); these genes were termed lupus sensitive interferon (LSI) responses. Importantly, 50 LSI response genes were significantly enriched among the dysregulated genes in CLE lesions (p=1.8×10-41), confirming their in vivo relevance. Binding sites for the transcription factor PITX1 were significantly enriched (p=2×10-4) in the LSI genes, suggesting a role for PITX1 in regulation of IFN responses. Indeed, PITX1 expression was increased in CLE lesions, and knockdown of PITX1 expression in N/TERT keratinocytes significantly abrogated interferon response gene expression after type I IFN, but not TNFα stimulation.
Conclusion: SLE patients exhibit increased interferon signatures in their skin secondary to increased production and a robust, skewed IFN response that is regulated by PITX1. Targeting of these exaggerated pathways may prove to be beneficial to prevent and treat hyperinflammatory responses in SLE skin.
To cite this abstract in AMA style:Tsoi A, Hile G, Berthier CC, Sarkar M, Reed TJ, Uppala R, Patrick M, Raja K, Xing X, He K, Gudjonsson J, Kahlenberg M. Lupus Keratinocytes Exhibit Skewed Interferon Responses and Dysregulation of a Novel Regulator of Interferon Signaling [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/lupus-keratinocytes-exhibit-skewed-interferon-responses-and-dysregulation-of-a-novel-regulator-of-interferon-signaling/. Accessed August 23, 2019.
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