State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, China.
Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong 510006, China.
Theranostics. 2020 Aug 21;10(23):10466-10482. doi: 10.7150/thno.45211. eCollection 2020.
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. 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. 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) and CD8 resident memory T (T) 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 CD44CD62L T in psoriatic mice, whereas methotrexate (MTX) lowered CD4, but not CD8, T 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 CD8CLA, CD8CD69 or CD8CD103 T 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 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 and CD103 T cells in humanized mice. We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8 T-cells.
常规免疫抑制剂会产生副作用，并且不能预防自身免疫性疾病的复发。此外，它们可能无法抑制致病性记忆 T 细胞介导的自身免疫。二氢青蒿素 (DHA) 已被证明可调节自身免疫。然而，DHA 是否影响银屑病及其复发仍不清楚。本研究旨在确定 DHA 对银屑病及其复发的治疗作用及其潜在机制。我们建立了咪喹莫特 (IMQ) 诱导的银屑病样野生型小鼠和接受来自银屑病患者皮损的人源化 NSG 小鼠的动物模型。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 Western blot。我们发现 DHA 不仅改善了银屑病小鼠的急性皮肤损伤，还通过减少 CD8 中央记忆 T (T) 和 CD8 驻留记忆 T (T) 细胞来减轻其复发。它减轻了 IMQ 诱导的银屑病小鼠的表皮病理学和 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 降低了银屑病小鼠中 CD8 的频率和数量，但不降低 CD4 的频率和数量，而甲氨蝶呤 (MTX) 降低了 CD4，但不降低 CD8 的频率和数量。事实上，DHA 而非 MTX 下调了 CD8 T 细胞中的 eomesodermin (EOMES) 和 BCL-6 表达。此外，DHA 而非 MTX 降低了 CD8 CLA、CD8 CD69 或 CD8 CD103 T 细胞在小鼠皮肤中的存在。有趣的是，在银屑病发作的第一阶段用 DHA 治疗，在两周后用低剂量 IMQ 诱导的银屑病复发中，很大程度上预防了银屑病的复发。用重组 IL-15 或 CD8，但不是 CD4，T 细胞处理可导致以前用 DHA 治疗的小鼠完全复发银屑病。最后，我们证明 DHA 减轻了移植有银屑病患者皮损的人源化 NSG 小鼠的银屑病人类皮肤损伤，同时减少了人源化小鼠中的人 CD8 T 和 CD103 T 细胞。我们首次提供了证据表明，DHA 通过减少记忆 CD8 T 细胞，在预防银屑病复发方面优于 MTX。
