A Critical Role of the IL-1 beta-IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis

The IL-1 signaling pathway has been shown to play a critical role in the pathogenesis of chronic, auto-inflammatory skin diseases such as psoriasis. However, the exact cellular and molecular mechanisms have not been fully understood. Here, we show that IL-1 beta is significantly elevated in psoriatic lesional skin and imiquimod-treated mouse skin. In addition, IL-1R signaling appears to correlate with psoriasis disease progression and treatment response. IL-1 signaling in both dermal gamma delta T cells and other cells such as keratinocytes is essential to an IMQ-induced skin inflammation. IL-1 beta induces dermal gamma delta T cell proliferation and IL-17 production in mice. In addition, IL-1 beta stimulates keratinocytes to secrete chemokines that preferentially chemo-attract peripheral CD27(-) CCR6(+)IL-17 capable of producing gamma delta T cells (gamma delta T17). Further studies showed that endogenous IL-1 beta secretion is regulated by skin commensals to maintain dermal gamma delta T17 homeostasis in mice. Mouse skin associated with Corynebacterium species, bacteria enriched in human psoriatic lesional skin, has increased IL-1 beta and dermal gamma delta T17 cell expansion. Thus, the IL-1 beta-IL-1R signaling pathway may contribute to skin inflammation and psoriasis pathogenesis via the direct regulation of dermal IL-17-producing cells and stimulation of keratinocytes for amplifying inflammatory cascade.