Conventional immunosuppressants cause side effects and do not prevent the recurrence of autoimmune diseases. Moreover, they may not inhibit autoimmunity mediated by pathogenic memory T-cells. Dihydroartemisinin (DHA) has been shown to regulate autoimmunity. However, it remains unknown whether DHA impacts psoriasis and its recurrence. The objective of this study was to determine therapeutic effects of DHA on psoriasis and its relapse as well as its underlying mechanisms./nMethods: We established animal models of imiquimod (IMQ)-induced psoriasis-like wild-type mice and humanized NSG mice receiving lesional human skin from patients with psoriasis. Many immunoassays, including immunohistochemistry, flow cytometry, quantitative RT-PCR and Western blotting, were performed./nResults: We found that DHA not only ameliorated acute skin lesion of psoriatic mice, but also alleviated its recurrence by diminishing CD8⁺ central memory T (T_CM) and CD8⁺ resident memory T (T_RM) cells. It attenuated epidermal pathology and T-cell infiltration in the skin of IMQ-induced psoriatic mice while suppressing expression of IL-15, IL-17 and other proinflammatory cytokines in the skin. Surprisingly, DHA reduced the frequency and number of CD8⁺, but not CD4⁺, subset of CD44^highCD62L^high T_CM in psoriatic mice, whereas methotrexate (MTX) lowered CD4⁺, but not CD8⁺, T_CM frequency and number. Indeed, DHA, but not MTX, downregulated eomesodermin (EOMES) and BCL-6 expression in CD8⁺ T-cells. Furthermore, DHA, but not MTX, reduced the presence of CD8⁺CLA⁺, CD8⁺CD69⁺ or CD8⁺CD103⁺ T_RM cells in mouse skin. Interestingly, treatment with DHA, but not MTX, during the first onset of psoriasis largely prevented psoriasis relapse induced by low doses of IMQ two weeks later. Administration of recombinant IL-15 or CD8⁺, but not CD4⁺, T_CM cells resulted in complete recurrence of psoriasis in mice previously treated with DHA. Finally, we demonstrated that DHA alleviated psoriatic human skin lesions in humanized NSG mice grafted with lesional skin from psoriatic patients while reducing human CD8⁺ T_CM and CD103⁺ T_RM cells in humanized mice./nConclusion: We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8⁺ T-cells.

中文翻译：

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双氢青蒿素通过减少野生型和人源化小鼠的 CD8+ T 细胞记忆来改善银屑病皮肤炎症及其复发。

常规免疫抑制剂会引起副作用并且不能防止自身免疫性疾病的复发。此外，它们可能不会抑制由致病性记忆 T 细胞介导的自身免疫。双氢青蒿素 (DHA) 已被证明可以调节自身免疫。然而，DHA 是否影响银屑病及其复发仍然未知。本研究的目的是确定 DHA 对银屑病及其复发的治疗作用及其潜在机制。/n 方法：我们建立了咪喹莫特 (IMQ) 诱导的银屑病样野生型小鼠和人源化 NSG 小鼠的动物模型接受银屑病患者的损伤人体皮肤。进行了许多免疫测定，包括免疫组织化学、流式细胞术、定量 RT-PCR 和蛋白质印迹法。/n结果：我们发现 DHA 不仅改善了银屑病小鼠的急性皮肤损伤，而且还通过减少 CD8 ⁺中枢记忆 T (T _CM ) 和 CD8 ⁺常驻记忆 T (T _RM ) 细胞来减轻其复发。它减弱了 IMQ 诱导的银屑病小鼠皮肤中的表皮病理和 T 细胞浸润，同时抑制了皮肤中 IL-15、IL-17 和其他促炎细胞因子的表达。令人惊讶的是，DHA 降低了 CD8 ⁺的频率和数量，但不是 CD4 ⁺，CD44^高CD62L^高T _CM在银屑病小鼠中的子集，而甲氨蝶呤 (MTX) 降低了 CD4 ⁺而不是 CD8 ⁺，_中医的频率和数量。事实上，DHA 而非 MTX 会下调 CD8 ⁺ T 细胞中的嗜中胚层蛋白 (EOMES) 和 BCL-6 的表达。此外，DHA 而非 MTX 减少了小鼠皮肤中 CD8 ⁺ CLA ⁺、CD8 ⁺ CD69 ⁺或 CD8 ⁺ CD103 ⁺ T _RM细胞的存在。有趣的是，在银屑病首次发作期间使用 DHA 而不是 MTX 治疗在很大程度上防止了两周后低剂量 IMQ 诱发的银屑病复发。给予重组 IL-15 或 CD8 ⁺而不是 CD4 ⁺ , T _CM细胞导致先前用 DHA 治疗的小鼠的银屑病完全复发。最后，我们证明 DHA 减轻了移植银屑病患者病变皮肤的人源化 NSG 小鼠的银屑病人类皮肤病变，同时减少了人源化小鼠中的人类 CD8 ⁺ T _CM和 CD103 ⁺ T _RM细胞。/n结论：我们提供了第一个证据通过减少记忆 CD8 ⁺ T 细胞，DHA 在预防银屑病复发方面优于 MTX 。