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<p>In psoriatic lesions, interleukin (IL)-17C protein expression has been reported as high as 125 times that of IL-17A; as such, it is crucial to understand the role that IL-17C plays in psoriasis, inflammation, and treatment response. Overexpression or injection of IL-17C in mice results in increased epidermal thickening and inflammation, whereas psoriatic mice with IL-17C knockout have decreased disease severity compared with control littermates. In psoriasis, IL-17C likely acts as a critical inflammatory amplifier via a feed-forward mechanism, wherein IL-17-producing CD4<sup>+</sup> helper T (T<sub>H</sub>17) cells and IL-17-producing CD8<sup>+</sup> cytotoxic T (T<sub>C</sub>17) cells stimulate IL-17C expression in keratinocytes. Then, keratinocyte-derived IL-17C induces IL-17A expression in T<sub>H</sub>17 and T<sub>C</sub>17 cells. Additionally, keratinocyte-derived IL-17C propagates its own signaling in an autocrine manner. Furthermore, studies suggest that IL-17C acts as an early mediator of psoriasis. No approved therapies directly target IL-17C. Brodalumab is an IL-17 receptor (IL-17R) A antagonist that inhibits IL-17A, F, C, and E signaling and has a unique mechanism of action among biologic therapies for psoriasis. By way of IL-17RA blockade, brodalumab is the only approved therapy for psoriasis that inhibits IL-17C signaling. This unique mechanism of action is hypothesized to correlate with efficacy in patients with prior failures to anti–IL-17A therapies and relatively higher rates of early skin clearance compared with those of other biologic therapies. Clinical studies are needed to confirm these correlations. In summary, IL-17C is an inflammatory amplifier and early psoriatic mediator, and inhibition of IL-17C may be beneficial in psoriasis management.</p>

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IL-17C as a Driver of Inflammation in Psoriasis

  • 期刊论文

  • 发表日期：

    2025年9月23日

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  • George Han,
  • April Armstrong,
  • James G. Krueger,
  • Abby Jacobson

摘要

In psoriatic lesions, interleukin (IL)-17C protein expression has been reported as high as 125 times that of IL-17A; as such, it is crucial to understand the role that IL-17C plays in psoriasis, inflammation, and treatment response. Overexpression or injection of IL-17C in mice results in increased epidermal thickening and inflammation, whereas psoriatic mice with IL-17C knockout have decreased disease severity compared with control littermates. In psoriasis, IL-17C likely acts as a critical inflammatory amplifier via a feed-forward mechanism, wherein IL-17-producing CD4+ helper T (TH17) cells and IL-17-producing CD8+ cytotoxic T (TC17) cells stimulate IL-17C expression in keratinocytes. Then, keratinocyte-derived IL-17C induces IL-17A expression in TH17 and TC17 cells. Additionally, keratinocyte-derived IL-17C propagates its own signaling in an autocrine manner. Furthermore, studies suggest that IL-17C acts as an early mediator of psoriasis. No approved therapies directly target IL-17C. Brodalumab is an IL-17 receptor (IL-17R) A antagonist that inhibits IL-17A, F, C, and E signaling and has a unique mechanism of action among biologic therapies for psoriasis. By way of IL-17RA blockade, brodalumab is the only approved therapy for psoriasis that inhibits IL-17C signaling. This unique mechanism of action is hypothesized to correlate with efficacy in patients with prior failures to anti–IL-17A therapies and relatively higher rates of early skin clearance compared with those of other biologic therapies. Clinical studies are needed to confirm these correlations. In summary, IL-17C is an inflammatory amplifier and early psoriatic mediator, and inhibition of IL-17C may be beneficial in psoriasis management.