Ultraviolet B Induces Cutaneous Lupus Erythematosus by Triggering a Ribotoxic-Stress-Response-Dependent MIF-p38 Feedback Loop in Keratinocytes

Abstract

Ultraviolet B (UVB) is one of the most common triggers of cutaneous lupus erythematosus (CLE), but the mechanism is still unclear. Here, we discovered that the expression of macrophage migration inhibitory factor (MIF), a multipotent cytokine, was significantly increased in keratinocytes of lupus patients in scRNA-seq data and clinical samples. We further discovered that UVB exposure induced MIF releasing from lupus keratinocytes and contributed to the tissue remodeling and inflammation by regulating the expression of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines in keratinocytes and fibroblasts. Mechanistically, UVB exposure triggered a ribotoxic stress response (RSR) in lupus keratinocytes, which was featured by the increased level of phospho-ZAK. The RSR induced MIF releasing through the activation of p38 and GSDMD cleavage. The released MIF could further promote the activation of p38 through its receptor CD74, forming a positive feedback loop triggered by UVB exposure in lupus keratinocytes. Intradermal injection of a Mif-shRNA AAV significantly improved the skin lesions in lupus mice. To further investigate the potentials of MIF as a therapeutic target, we developed a microneedle patch capable of intradermal administration of a MIF inhibitor, which effectively protected lupus mice from skin lesions induced by UVB exposure. In conclusion, our findings suggest a novel mechanism by which UVB exposure contributes to the development of CLE by triggering a positive feedback loop of MIF-p38 in lupus keratinocytes. Our results also demonstrate the translational potentials of microneedle patch targeting MIF in the treatment of CLE.