Cutaneous inflammation is a prevalent and often difficult to treat manifestation of systemic lupus erythematosus (SLE) that is frequently associated with and may lead to exacerbation of systemic disease. There is a critical need to understand the mechanisms behind why SLE skin is prone to inflammation in order to improve therapies and outcomes for skin disease patients. Type I interferon (IFN) responses are elevated in cutaneous lupus erythematosus (CLE) lesions and prime keratinocytes for inflammatory responses to ultraviolet light exposure. Importantly, SLE keratinocytes display an exaggerated response to IFN? for some, but not all, type I IFN regulated genes. These SLE-IFN-skewed genes likely play a critical role in promoting the enhanced inflammatory response in SLE keratinocytes One of these SLE-IFN-skewed genes is BATF2, an understudied transcription factor that interacts with interferon regulatory factor 1 (IRF-1) to regulate inflammatory gene production. These preliminary data suggest that BATF2 may serve as an excellent target to modulate inflammatory responses in the skin and thus to prevent and treat cutaneous inflammation in SLE. We hypothesize that exaggerated inflammatory responses in SLE keratinocytes are driven through IFN- mediated hyper-upregulation of BATF2. Testing of this hypothesis through the following Aims will identify a mechanism by which IFNs promote inflammatory signaling in SLE keratinocytes and identify BATF2 as a potential therapeutic target for controlling cutaneous inflammation in SLE Aim 1: Identify BATF2 as a crucial mediator of pro-inflammatory cytokines and chemokines following type I IFN priming of keratinocytes.
Aim 2 : Identify the role of BATF2 in regulation of type I vs. type II IFN responses in keratinocytes and how this is regulated by IRFs. Completion of these Aims will identify BATF2 as a regulator of inflammatory responses in keratinocytes and as a target for decreasing keratinocyte-derived inflammation in lupus skin. Further, this project will compare how type I and type II IFNs, both of which are identified as important in SLE skin, induce inflammatory changes through BATF2. This information will have important implications as type I IFN-directed therapy becomes mainstream in SLE.
Cutaneous lupus lesions are disfiguring, difficult to treat, and often associated with flares of systemic lupus that lead to organ damage and disability. This project will uncover novel mechanisms that drive the development of cutaneous lupus lesions and will ultimately lead to new preventative and therapeutic strategies for this devastating disease. Discoveries made through this research are directly relevant to the NIH's mission to foster fundamental discoveries and their applications to protect and improve public health.