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Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation

Interleukin-17 receptor D serves as a functional receptor for Interleukin-17A in psoriasis-like skin inflammation. A new receptor for interleukin-17 The cytokines interleukin-17A (IL-17A) and IL-17F drive immune activation by binding to the IL-17 receptor (IL-17R) complex composed of two subunits, IL-17RA and IL-17RC. Here, Su et al. identify a second IL-17R complex composed of IL-17RA and IL-17RD that is expressed by skin keratinocytes. Using a mouse model of psoriasis, they report that IL-17RA/IL-17RD complex plays a vital role in driving IL-17–dependent skin inflammation. Although the IL-17RA/IL-17RC complex binds IL-17A and IL-17F homodimers and IL-17A/IL-17F heterodimers, they report here that the IL-17RA/IL-17RD specifically binds IL-17A homodimers. As antibodies targeting IL-17 cytokines and their receptors are being used in the treatment of autoimmune diseases, the discovery of a second receptor is interesting from both basic and clinical viewpoints. T helper 17 (TH17) cells and interleukin-17A (IL-17A) produced by them are critical in autoinflammatory diseases, such as psoriasis. IL-17A has been shown to signal through IL-17 receptor A/IL-17 receptor C (IL-17RA/IL-17RC) complex to drive inflammatory responses. However, in a psoriasis model, we found that Il17rc deficiency did not completely ameliorate the disease, suggesting another receptor. In search for another IL-17A–interacting receptor, we found that IL-17RD directly bound IL-17A but not IL-17F or IL-17A/F heterodimer and formed a heterodimer with IL-17RA. IL-17A–, but not IL-17F– or IL-17A/F–, mediated gene expression was defective in Il17rd-deficient keratinocytes. Il17rd deficiency in nonhemopoietic cells attenuated imiquimod-induced psoriasis-like skin inflammation. Although IL-17RC and IL-17RD differentially activated IL-17A–dependent signaling and gene expression, their compound mutation led to complete deficits in keratinocytes. IL-23 was found induced by IL-17A in keratinocytes, dependent on both IL-17RC and IL-17RD, suggesting feed-forward regulation of IL-23/IL-17 axis in psoriasis. Together, IL-17RD constitutes a second functional receptor for IL-17A and, together with IL-17RC, mediates the proinflammatory gene expression downstream of IL-17A.