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

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Published:7th Jun 2019
Author: Su Y, Huang J, Zhao X, Lu H, Wang W, Yang XO et al.
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Ref.:Sci Immunol. 2019 Jun 7;4(36):eaau9657.
DOI:10.1126/sciimmunol.aau9657
Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation


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.


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