TWEAK and Skin Inflammation - ABSTRACT
Skin inflammatory diseases, such as atopic dermatitis and psoriasis, are thought to be driven by the interplay
between the immune system and structural cells present in the epidermis or dermis. Features of these
diseases include tissue remodeling which can be excessive deposition of collagen and other extracellular
matrix proteins in the dermal and/or adipose layers, vascular damage, immune cell infiltration, and/or
epidermal hyperplasia. Primary cells that can contribute to skin inflammation include T cells, fibroblasts,
keratinocytes, and macrophages, with additional contributions of neutrophils, mast cells, and eosinophils
depending on the specific disease. Collagen and other extracellular matrix protein deposition is thought
mediated primarily by deregulation of fibroblasts, and driven by secreted products from inflammatory cells like
Th2 or Th17 cells. These cytokines, which include IL-13 or IL-17, also contribute to end-stage pathology in
atopic dermatitis and psoriasis, through direct actions in promoting epidermal hyperplasia and through
production of additional soluble mediators such as chemokines from keratinocytes. The discovery of new and
novel protein targets that perform similar, alternate, or synergistic actions is of strong interest, especially if
these proteins are active in promoting skin inflammation in both atopic dermatitis and psoriasis. We have
recently shown that a TNF family protein, called TWEAK (TNFSF12), that interacts with the TNFR superfamily
molecule Fn14, when injected into the skin of mice, can promote features of both atopic dermatitis and
psoriasis, including dermal and epidermal thickening, and upregulation of inflammatory cytokines that are seen
in patients with both diseases. Correspondingly, mice that are deficient in TWEAK are strongly protected from
developing skin inflammation in models of atopic dermatitis and psoriasis. From analysis of human cells, we
have found that Fn14 is expressed in keratinocytes and dermal fibroblasts, and preliminary data suggests that
TWEAK can have strong effects on these cells linked to skin inflammation. This proposal will focus on in vivo
mouse models of atopic dermatitis and psoriasis, complemented with in vitro studies of mouse and human
structural cells implicated in driving skin inflammation, and determine how TWEAK contributes to skin
inflammatory disease, delineate what are its cellular and molecular targets, understand how TWEAK signals
integrate with those from IL-13 and IL-17, and test whether TWEAK and Fn14 represent new targets for
therapeutically dampening or reversing skin inflammatory disease.
