Background/Purpose: Photosensitivity is a major symptom of lupus, and excessive sunlight can cause skin rashes and flares of disease activity in systemic lupus erythematosus (SLE). Although UV-induced skin inflammation has been widely studied, it remains elusive how UV triggers lupus. A previous study demonstrated that mice lacking the Ro60 autoantigen (Ro60^–/–) have increased photosensitivity and spontaneously develop lupus after 6 months of age. Also, it has been shown that lupus patients have elevated levels of type I interferon (IFN). To dissect molecular mechanisms by which UV-induced inflammatory responses are exacerbated in lupus, we combined IFN priming with photosensitive Ro60^–/– mice and investigated the effects of UV on lupus-prone skin.

Methods: A recombinant adenovirus encoding IFN-alpha was administered to 4–5-month-old mice by retro-orbital injection two weeks prior to UV irradiation (IFN priming). Subsequently, mice were irradiated with UVB 250 mJ/cm²/day for three consecutive days. Skin biopsies were taken at four time points and subjected to histological, flow cytometry, and gene expression analyses. Eight groups (n = 4 mice per group) were compared: wild type (WT) versus Ro60^–/– (C57BL/6 background), male versus female, and with or without IFN priming.

Results: Three consecutive UV exposures caused severe skin damage (erythema and hyperkeratosis) in IFN-primed Ro60^–/– females. Gene expression analysis of UV-irradiated skin revealed that many inflammatory genes were differentially upregulated among the 8 mouse groups. Specifically, a combination of IFN priming, Ro60 deficiency, and female gender augmented UV-induced upregulation of Irf7 (regulator of type I IFN gene induction), Isg15 (IFN-stimulated gene), and Ccl2 (chemokine for monocyte recruitment). Consistently, flow cytometry analysis revealed that more inflammatory monocytes (CD45⁺Ly6C^highLy6G^low) were recruited to UV-irradiated skin 1 day after the third UV in IFN-primed Ro60^–/– females than in IFN-primed WT females. Intriguingly, IFN-primed Ro60^–/– females exhibited significantly higher levels of Ifnar2 (IFN alpha receptor subunit 2) following UV than their WT counterparts, likely contributing to augmented type I IFN responses.

Conclusion: Inflammatory responses to UV irradiation were augmented in IFN-primed Ro60^–/– female, but not in WT, male, or unprimed mice. This female predominance is comparable to that of SLE in humans. Ro60 is an RNA-binding protein and binds to small noncoding RNAs. Lack of Ro60 may disrupt RNA homeostasis and activate RNA sensors and type I IFN pathways. This study provides novel insight into lupus susceptibility factors (IFN priming, Ro60 deficiency, and female gender) that contribute to exacerbation of UV-induced skin inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/uv-induced-skin-inflammation-is-exacerbated-in-lupus-prone-ro60-knockout-female-mice-with-interferon-priming/