Epidermal activation of the small GTPase Rac1 in psoriasis pathogenesis

Abstract

The small GTPase Ras-related C3 botulinum toxin substrate 1 (RAC1) plays a central role in skin homeostasis, including barrier function, wound healing and inflammatory responses. Psoriasis is a common skin disease characterized by deregulation of these functions, and affected skin exhibit keratinocyte hyperproliferation, inflammation and immune cell infiltration. Although psoriasis is often triggered by environmental stimulus, there is a strong genetic association with genes expressed in both immune cells and keratinocytes, of which several are linked to Rac1 signaling. Rac1 is highly active in human psoriatic lesional skin and keratinocytes, and keratinocyte-specific overexpression of an activated mutant of Rac1, Rac1^V12, in a transgenic mouse model closely mimics the presentation of human psoriasis. Both Rac1 activation in keratinocytes and immune derived stimulus are required to drive psoriasiform signaling in transgenic mouse and human xenograft models of psoriasis. Therefore, understanding how increased Rac1 activation in psoriatic epidermis is regulated is central to understanding how the abnormal crosstalk between keratinocytes and immune cells is maintained.

Keywords: Rac1; crosstalk; epidermis-immune; keratinocyte; psoriasis.

Figure 1.

Potential upstream factors involving innate immune responses could lead to Rac1 activation in psoriatic keratinocytes and propagating a pathogenic epidermal-immune feedback loop. β-defensins, LL 37 and DOCK/ELMO signaling are examples involving innate immune signaling that both can activate Rac1 in epithelial cells and are implicated in psoriasis pathogenesis. High Rac1 activation perturbs differentiation signals central for skin barrier integrity, and leads to production of chemotactic and immunocyte-activating cytokines. Immune-derived stimulus propagates psoriasiform signaling pathways in keratinocytes involving STAT3, NFκB and interferon signaling and lead to subsequent hyperproliferation, inflammation and a perturbed skin barrier.