High Humidity Exacerbates Psoriasiform Skin Disease Relapse by Increasing Tissue‐Resident Memory T Cells via Altering Skin Microbiota

ABSTRACT Psoriasis recurrence remains a common and difficult medical problem, while environmental humidity appears to have an impact on psoriasis morbidity. However, it remains unknown whether and how high humidity impacts psoriasis relapse. Using unique mouse models of psoriasis relapse, we found that high humidity exposure exacerbated psoriasis recurrence by increasing skin‐resident memory CD8 ⁺ T (T _RM ) cells through a mechanism depending on its upregulation of IL‐15Rα on keratinocytes. Keratinocyte‐specific knockout of IL‐15Rα or administrating soluble sIL‐15Rα to block IL‐15 abrogated these effects. Moreover, the effects of high humidity on psoriasis relapse, IL‐15Rα expression and skin T _RM cell formation were attributed to cutaneous Staphylococcus nepalensis since its recolonization or its specific metabolite, asymmetric dimethylarginine (ADMA), upregulated IL‐15Rα expression on keratinocytes, increased skin CD8 ⁺ T _RM cells and worsened psoriasis relapse. However, treatment with mupirocin, an antibiotic, alleviated recurrent psoriasis. In vitro experiments showed that culture supernatant of Staphylococcus nepalensis upregulated IL‐15Rα expression on keratinocytes, while IL‐15Rα‐expressing keratinocytes promoted formation of CD8 ⁺ T _RM phenotypes. Finally, high humidity also aggravated psoriatic skin lesions in humanized mice. Thus, our findings enhanced a new understanding of how climatic factors govern psoriasis recurrence and unveiled a role for IL‐15Rα‐expressing keratinocytes in skin CD8 ⁺ T _RM formation and psoriasis relapse.