Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-induced Lupus Model

Gantsetseg Tumurkhuu¹, Shuang Chen², Erica Montano¹, Malcolm Lane², Michifumi Yamashita², Janet Markman², Luz Blanco³, Mariana Kaplan⁴, Kenichi Shimada², Timothy Crother², Mariko Ishimori², Daniel J Wallace¹, Caroline Jefferies⁵ and Moshe Arditi², ¹Cedars-Sinai Medical Center, Los Angeles, ²Cedars-Sinai Medical Center, Los Angeles, CA, ³National Institute of Arthritis and Musculoskeletal and Skin Diseases, Centreville, ⁴National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, ⁵Cedars-Sinai Medical Center, West Hollywood, CA

Meeting: ACR Convergence 2020

Keywords: interferon, Mouse Models, Lupus, skin

Session Information

Date: Friday, November 6, 2020

Title: SLE – Etiology & Pathogenesis Poster

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2′-deoxyguanosine(8-OH-dG), in the pristane-induced mouse model of SLE.

Methods: C57/Bl6 (WT) and Ogg1 KO mice were injected i.p. with 0.5ml of pristane or PBS as control (WT-PBS). In order to observe the effects of Ogg1 deficiency in fully developed SLE, we analyzed the mice 10 months after induction. Histological features of skin and kidney were quantified by an image analysis system. Serum total IgG, IgG subtypes (IgG1 and IgG2a), and autoantibodies ( anti-dsDNA and anti-RNP) were measured by ELISA. Gene expression analysis for IFN and ISG genes was performed by RT-PCR using SYBR green.
Immune cell types were analyzed separately for each mouse by standard FACS procedures. Peripheral blood mononuclear cells (PBMCs) were separated from whole blood by density-gradient centrifugation with Ficoll-Paque Plus (GE Healthcare). CD14⁺ monocytes were purified from fresh PBMCs by positive selection using magnetic CD14⁺ beads (Miltenyi Biotec) according to the manufacturer’s protocol

Results: Ogg1^-/- mice developed an exacerbated disease profile, characterized by aggravated skin pathology, increased auto-antibodies, higher total IgG, and higher splenic cell number. Neutrophils from pristane-treated Ogg1^-/-mice exhibited earlier NETosis compared to WT. BMDMs from Ogg1^-/-mice produced increased basal and cGAMP-driven IFN-β expression, which was diminished by treatment with the STING inhibitor H151, and skin lesions from pristine-treated Ogg1^-/- mice had significantly higher expression of type I IFN genes than lesions in WT mice. Finally, expression of OGG1 was significantly lower in lesioned skin compared with non-lesioned skin in Discoid Lupus patients.

Conclusion: In conclusion, our study clearly supports a crucial role for OGG1 in protecting against IFN production and SLE skin disease.

Disclosure: G. Tumurkhuu, None; S. Chen, None; E. Montano, None; M. Lane, None; M. Yamashita, None; J. Markman, None; L. Blanco, None; M. Kaplan, None; K. Shimada, None; T. Crother, None; M. Ishimori, None; D. Wallace, None; C. Jefferies, None; M. Arditi, None.

To cite this abstract in AMA style:

Tumurkhuu G, Chen S, Montano E, Lane M, Yamashita M, Markman J, Blanco L, Kaplan M, Shimada K, Crother T, Ishimori M, Wallace D, Jefferies C, Arditi M. Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-induced Lupus Model [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/oxidative-dna-damage-accelerates-skin-inflammation-in-pristane-induced-lupus-model/. Accessed .

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