Stromal-Immune Interactions in Priming for and Maintaining Inflammation in Lupus Skin (Project 1)

PROJECT SUMMARY/ABSTRACT (Project 1) Skin inflammation is a prominent and visible manifestation of systemic lupus erythematosus (SLE), with about 70% of SLE patients experiencing cutaneous eruptions under the category of cutaneous lupus erythematosus (CLE). Despite skin being a prominent target organ in lupus, research in SLE has primarily been focused on the role of immune cell populations, such as plasmacytoid dendritic cells, with scant attention given to the role and contribution of stromal cells, including keratinocytes, fibroblasts, and endothelial cells. This project of the University of Michigan Integrated Program for Cutaneous Immune-Stromal interactions in SLE (IPCISS) will build upon an accomplished collaborative working group seeking to understand the etiologies of CLE and SLE. Our work has shown dysregulation of interferon and inflammatory signaling in lupus keratinocytes and other stromal cell populations in non-lesional and lesional lupus skin with highly dynamic cell-cell interactions between stromal cells and components of the immune system. This project will address the hypothesis that stromal cell responses are critical in maintaining and shaping inflammatory responses in CLE skin. Our specific aims are Aim 1: Dissect the crosstalk between stromal and immune cells in lupus skin and determine how this crosstalk primes for and maintains type I IFN responses. Our hypothesis is that type I IFN responses are driven by both spatial and temporal interactions between immune cells (i.e., pDCs) and KC in lupus skin. Aim 2: Determine the role of cell proximity and co-localization in CLE inflammatory responses. Our hypothesis is that inflammation in CLE skin is highly compartmentalized with inflammation focused on hair follicle niches and epidermal-dermal junction. Aim 3: Identify chromatin modifications and “inflammatory memory” in SLE stromal cells, and reversibility with treatment. Our hypothesis is that stromal cells in CLE skin have chromatin modeling/epigenetic modifications that maintain inflammation and promote relapses. Together with Project 2, this project will address hitherto unexplored avenues of skin inflammation in lupus and will help define the role of stromal cells in both the immunopathogenesis of active disease, as well as contribution to disease flares. It will provide novel insights into CLE pathogenesis and ultimately facilitate the development of preventative therapies for this devastating disease.