Lupus erythematosus is a chronic, debilitating autoimmune disease that disproportionately affects women of childbearing age and has been found to be among the leadings causes of death in this population. The systemic form of the disease, systemic lupus erythematosus (SLE), has heterogeneous clinical manifestations that can affect nearly all major organs of the body. When there is skin involvement, the disease is grouped under the category of cutaneous lupus erythematosus (CLE). CLE can occur on its own or in combination with systemic disease with up to 70% of SLE patients experiencing cutaneous involvement. Both SLE and CLE are characterized by increased sensitivity to ultraviolet (UV) light. UV light can trigger cutaneous and systemic disease flares that severely diminish patient quality of life and carry significant economic burdens. As the mechanisms driving these responses are not understood, few treatment options exist with prevention largely based on sun avoidance and sunscreen use. Type I interferons (IFNs), a group of cytokines generally produced in response to viral infection, are chronically overexpressed in lupus patients with circulating levels correlating with cutaneous disease activity. Type I IFNs regulate expression of several genes that may play a role in photosensitivity including pro-apoptotic Xaf1 and chemokines that promote natural killer (NK) cell recruitment and activation. The Kahlenberg laboratory previously observed that type I interferons (IFNs) are increased at baseline in SLE keratinocytes (KCs) and promote cell death after UV exposure. However, the specific pathways regulated by type I IFNs that enhance UV-driven KC death are not known. This proposal will test the hypothesis that chronic overexpression of type I IFNs in lupus skin primes keratinocytes for increased UVB-induced extrinsic apoptosis through upregulated XAF1 expression and enhanced recruitment and activation of cytotoxic NK cells. This hypothesis will be tested through three specific aims: (1) Examine activation of extrinsic vs. intrinsic apoptosis in type I IFN-primed skin following UVB exposure, (2) Determine the role of XAF1 in type I IFN-driven KC apoptosis, and (3) Identify the role of NK cells in type I IFN-driven KC apoptosis. To accomplish these specific aims, human cell lines and genetically engineered mouse models will be used to perform in vitro and in vivo experiments investigating cell signaling and genetic regulation of type I IFN-primed KCs exposed to UV light and to determine how this influences NK cells that are recruited into the skin. The results from these studies will establish the impacts of type I IFN overproduction in lupus skin in the context of photosensitivity with the overall future goal of identifying targets for new treatment options for patients whose disease is flared by the sun. This project will serve as a crucial mechanism through which the applicant will further expand her core skills in experimental design and data analysis, professional development, and scientific communication. The ample resources available at the University of Michigan together with experienced mentors and collaborators will ensure the applicant is able to successfully complete the proposed research and training plans.
Lupus is a debilitating autoimmune disease characterized by overproduction of type I interferons (IFNs) and abnormal responses to sunlight that can drive cutaneous and systemic flares of disease. Our preliminary data suggest that type I IFNs in the skin drive enhanced keratinocyte apoptosis after exposure to ultraviolet (UV) light. This project aims to understand how type I IFNs make keratinocytes more sensitive to dying and how this may lead to immune system activation that exacerbates inflammation with the goal of identifying potential therapeutic targets for patients suffering from this devastating disease.
