Understanding innate immune cell-mediated inflammation in UV-induced skin injury in lupus-prone mice.

Abstract

Abstract Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by sensitivity to ultraviolet (UV) light and overproduction of type I interferons (IFNs), in which skin is affected in up to 70% of total SLE patients. While UV light is one of few well-known triggers of SLE, precise mechanisms governing UV-mediated inflammation are incompletely understood. Our lab recently performed single-cell analysis of cutaneous lupus lesions, showing an increase in activated monocyte-derived CD16+ dendritic cells (DCs) in both lesional and non-lesional skin of lupus patients compared with healthy controls. With the goal of understanding the functionality of this subset, we have turned to lupus-prone murine models. RNA sequencing of UV-exposed skin samples from lupus-prone NZM2328 (NZM), iNZM (lupus-prone mice lacking the type I IFN receptor) and wildtype Balb/c mice demonstrated upregulation of monocyte chemoattractants like CCL2 in NZM greater than iNZM and Balb/c, which was verified at the transcript and protein level of UV-irradiated human lupus keratinocytes compared with healthy controls. We further verified recruitment and differentiation of monocytes into monocyte-derived DCs (moDC) in UV-irradiated skin of NZM, iNZM, and Balb/c mice, as well as increased MHC class II expression in skin-recruited moDCs of chronically UV-exposed NZM mice greater than iNZM and Balb/c, suggesting an importance of type I IFN signaling in this process. Future studies will be directed at understanding mechanisms of monocyte recruitment and differentiation at sites of UV-mediated inflammation, as well as type I IFN effects on moDC antigen uptake and presentation. Supported by grants from NIH (T32-GM007863, R01-AR071384, and K24-AR076975)