Background Patients with systemic lupus erythematosus (SLE) experience photosensitivity, with exposure to ultraviolet light (UV) driving lupus flares, triggering symptoms like joint pain and fatigue, in addition to causing cutaneous lesions. Our previous work has shown that TRIM21, an autoantigen in SLE, functions as a negative regulator on the pathways driving IFN expression. Trim21 ^-/- mice develop systemic autoimmunity due to an inability to regulate type I IFNs. These mice also spontaneously develop skin lesions, leading us to hypothesize that Trim21^-/- mice may have enhanced sensitivity to UV-induced skin inflammation.

Methods Wild type (WT, C57BL/6) and TRIM21 KO mice were irradiated with UVB (100 mJ/cm²) consecutively for 1 and 3 weeks, and blood, spleen and kidney analyzed by qPCR, histology, and flow cytometry. Bone marrow derived macrophages (BMDMs) and mouse skin fibroblasts (MDF) were analyzed by qPCR and western blotting. Peripheral blood samples from SLE patients were analyzed by qPCR for interferon stimulated genes (ISG) RSAD2, IFI44, IFI44L, IFI27 and used to calculate IFN scores.

Results Macroscopically, both WT and Trim21^-/- mice developed similar levels of erythema, edema and induction of inflammatory cytokines in response to UVB exposure. However, compared to WT mice, expression of IFNβ and ISGs were elevated in the skin of Trim21^-/- mice following UVB. Most notably after UVB exposure, we observed splenomegaly and enhanced expression of ISGs in the blood and spleen of Trim21^-/- mice. Trim21^-/- mice also demonstrated enhanced total IgG levels in serum, significantly increased deposition of IgG in the skin and increased ISG expression in the kidneys, all suggesting that loss of TRIM21 in mice results in enhanced IFN-driven responses systemically. Enhanced basal, UVB- and cGAMP-dependent IFNβ expression was observed in Trim21^-/- BMDMs and MDFs which was restored in BMDMs from Trim21^-/- /Sting^-/-, suggesting the cGAS-STING pathway was inappropriately regulated in these absence of TRIM21. As TRIM21 is an E3 ligase and known to regulate protein stability, we assessed levels of cGAS, DDX41 (a DNA sensor and regulator of STING signaling) and STING itself. Mechanistically, we found only DDX41 protein levels were stabilized in Trim21^-/- MDFs or BMDMs, respectively, suggesting it to be a target on this pathway.

Conclusions Taken together our results indicate that TRIM21 protects against IFN induction both at a local and systemic level in response to DNA sensing. Understanding the role of TRIM21 in preventing systemic disease will have important understandings of its role in driving increased disease activity and flare in SLE.

Acknowledgements Supported by Leon Fine Award in Translational Science and Center for Research in Women’s Health and Sex Differences, Cedars Sinai Medical Center.