Mechanisms Driving Inflammation in Psoriasis
The Role of IL-22/PLCε Signaling in Psoriasis
The outermost layer of the skin is the epidermis, which primarily functions as a protective mechanical barrier preventing the entry of harmful pathogens. The epidermis is predominantly composed of keratinocytes, but also contains other cell types like melanocytes, Langerhans cells, Merkel cells, and inflammatory cells.
Psoriasis is a chronic immune-mediated skin disease that causes red, itchy scaly patches to develop, most commonly on the knees, elbows, trunk, and scalp. This is caused by an acceleration of the normal life cycle skin cells, which leads to a buildup of dead cells on the surface of the epidermis. Inflammation caused by psoriasis can also impact other organs and tissues in the body with more than one-third of individuals developing more severe conditions like psoriatic arthritis. Inflammatory skin diseases are often thought to be associated with epidermal barrier defects.
The cytokine Interleukin (IL-22) is involved in skin homeostasis and is implicated in the pathogenesis of various skin diseases, such as psoriasis, atopic dermatitis, and skin cancer. Interaction of IL-22 with its receptor initiates an inflammatory cascade during normal responses to pathogens or skin barrier disruption. Dysfunction of this pathway results in the continuous release of pro-inflammatory molecules and can contribute to the development of immune disorders like psoriasis. Previous research has shown that phospholipase C epsilon (PLCε) plays a similar regulatory role to IL-22 where overexpression of epidermal PLCε induces psoriasis-like skin lesion and increases cytokine expression. Because of this, the authors of this recent publication were interested to define the link between IL-22 and PLCε in mediating the inflammatory in response to the disruption of the skin barrier.
To explore whether PLCε is involved in the inflammatory response to the disruption of the skin barrier, acute disruption of epidermal permeability barrier was induced in wild-type and PLCε knockout (KO) mice. mRNA levels for a number of inflammatory factors were lower in the PLCε KO mice than in wild-type mice confirming that removal of PLCε suppresses skin inflammatory responses.
Next, the authors looked at whether the decreased inflammatory response caused by PLCε deficiency is mediated by IL-22. Because the IL-22 receptor is highly expressed on keratinocytes and fibroblasts, the effect of IL-22 on inflammation was evaluated in fibroblasts derived from PLCε KO and wild-type mouse skin in vitro. IL-22 increased the expression levels of mRNA for cytokines, chemokines, and antimicrobial peptides in fibroblasts from wild-type mice, but had little effect on the fibroblasts from PLCε KO mice suggesting that PLCε has a critical role in IL-22-induced inflammation in fibroblasts.
Confirmatory gene silencing studies were performed using Lifeline’s primary human epidermal keratinocytes (HEKs) transfected with PLCε siRNA. Zhang and Colleagues found that mRNA levels of proinflammatory molecules were decreased following IL-22 stimulation in the transfected HEK cells, an indication that IL-22-mediated inflammation is at least in part controlled by PLCε and that IL-22 is likely upstream of the inflammatory cytokine cascades induced by barrier disruption.
The results of the present study suggest that the pathogenic role of IL-22 in psoriasis could be mediated by PLCε.
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