MAFB as a New Key Player Controlling Lymphatic Vessels in Psoriasis Pathogenesis
Supported by Karen and Dale White Research Center of Excellence
Layman's Statement: Psoriasis is an inflammatory disorder of the skin which affects about 2% of the entire population. The extra skin cells form scales and red patches that are itchy and sometimes painful. In psoriasis, uncontrolled proliferation of skin epithelial cells (keratinocytes) induces skin thickening. This event is accompanied by the accumulation of immune cells and inflammatory molecules in the inflamed tissue, skin swelling and dysfunction of blood and lymphatic vessels (LVs). In healthy tissue, there is a balance, homeostasis, between fluid and immune cells derived from blood vessels and the ones taken up and drained by the LVs away from the tissue. During psoriasis, inflammation dramatically changes LVs which become enlarged and incapable of draining properly, this results in an accumulation of inflammatory cells and molecules in the tissue further promoting inflammation. We have discovered that LVs in psoriasis have reduced levels of a protein called MAFB. MAFB is an important player in fine-tuning LV formation and is a crucial anti-inflammatory factor in other cell types. We hypothesize that MAFB regulates LV function and can restore a proper drainage in psoriasis. Therefore, we aim at correcting MAFB levels to normalize LVs, restore their proper activity, resolving inflammation and alleviating psoriasis symptoms.
Grant Abstract: Psoriasis is an inflammatory skin disorder which involves hyperproliferation of keratinocytes, inflammatory cell activation and infiltration, and vasculature remodeling. Lymphatic vessels (LVs) play a fundamental role in healthy skin by providing an efficient route for drainage of immune cells, inflammatory cytokines and antigens away from the tissue. In psoriasis, LVs are often functionally impaired and current studies aim at restoration of LV function to resolve inflammation. To better understand what prevents LVs to exert their crucial activities in psoriasis, we isolated and functionally characterized lymphatic endothelial cells (LECs) derived from the skin of patients with psoriasis vulgaris and from healthy controls admitted to plastic surgery. Patients derived LECs were viable and displayed a different behavior and gene expression profile compared with controls. More in detail, psoriatic LECs were hyperactivated and presented differential expression of 558 genes, most of which associated with inflammatory immune response. The transcription factor MAFB was among the most significantly differentially expressed genes. Similar to psoriatic LECs, we found that MAFB is downregulated in human LECs chronically treated with an inflammatory stimulus. MAFB is a leucine zipper DNA binding protein which regulates the differentiation of several cell types, including monocytes/macrophages, podocytes and epidermal keratinocytes. The research group of Professor Detmar recently discovered that MAFB is an important regulator of LV patterning during development. In inflammatory disorders, MAFB was demonstrated to promote resolution of inflammation and its levels were reduced in the skin of psoriatic patients. Based on published literature and our own original data, we believe that MAFB plays a pivotal role in psoriasis pathogenesis by controlling LV phenotype and function. Therefore, restoring MAFB levels in inflamed LVs could represent a potential therapeutic target to treat psoriasis. To address this hypothesis, we will take advantage of both in vitro and in vivo experiments to pursue the following aims: Aim1. Characterize MAFB expression and function on lymphatic vessels in human psoriasis; Aim 2. Assess the expression and function of MAFB in LVs in experimental models of psoriasis.