Department of Rheumatology and Immunology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China.
Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, China.
J Invest Dermatol. 2019 Sep;139(9):1946-1956.e3. doi: 10.1016/j.jid.2019.02.021. Epub 2019 Mar 13.
Psoriasis is a chronic inflammatory skin disease with unresolved pathogenesis. Studies on the pathogenesis of psoriasis have been extensively carried out, but treatments are still not satisfactory. In this study, we found improvement after treatment with cis-khellactone, a small molecular natural product, in imiquimod-challenged C57BL/6 mice. cis-Khellactone clearly reduced the level of cytokines in psoriatic skin, including IL-23, TNF-α, IL-1β, and IL-6, while limiting the inhibition of IL-17A, which is produced by T helper type 17 cells. cis-Khellactone treatment specifically decreased dermal macrophage infiltration in psoriatic skin but not in neutrophils or T cells. Additionally, compared with the control group, cis-khellactone significantly decreased the activation of NF-κB p65 in these infiltrated macrophages. Further study showed that cis-khellactone suppressed proinflammatory phenotypic macrophages by promoting autophagy. Blocking autophagy by silencing Beclin1 or Atg7 abrogated the effect of cis-khellactone on macrophages. The autophagy-dependent improvement in psoriasis from cis-khellactone treatment was further manifested by its limited effects on skin lesions in chloroquine-treated mice. Moreover, cis-khellactone showed lower toxicity levels than methotrexate in macrophages and primary hepatocytes. Taken together, cis-khellactone selectively modulated macrophage function and phenotype by inducing autophagy to ameliorate imiquimod-induced psoriasis in mice. Our research provides an effective strategy for the treatment of psoriasis.
银屑病是一种慢性炎症性皮肤病，其发病机制尚未得到解决。对银屑病发病机制的研究已经广泛开展，但治疗效果仍不尽人意。在本研究中，我们发现小分子天然产物顺式金合欢内酯治疗咪喹莫特诱导的 C57BL/6 小鼠后病情得到改善。顺式金合欢内酯明显降低了银屑病皮肤中细胞因子的水平，包括 IL-23、TNF-α、IL-1β 和 IL-6，同时限制了 Th17 细胞产生的 IL-17A 的抑制作用。顺式金合欢内酯治疗特异性减少了银屑病皮肤中的真皮巨噬细胞浸润，但对中性粒细胞或 T 细胞没有影响。此外，与对照组相比，顺式金合欢内酯明显降低了这些浸润巨噬细胞中 NF-κB p65 的激活。进一步的研究表明，顺式金合欢内酯通过促进自噬来抑制促炎表型的巨噬细胞。沉默 Beclin1 或 Atg7 阻断自噬可消除顺式金合欢内酯对巨噬细胞的作用。顺式金合欢内酯通过自噬依赖性改善银屑病的作用在氯喹处理的小鼠中得到了进一步体现，其对皮肤损伤的影响有限。此外，顺式金合欢内酯在巨噬细胞和原代肝细胞中的毒性水平低于甲氨蝶呤。综上所述，顺式金合欢内酯通过诱导自噬选择性调节巨噬细胞功能和表型，从而改善小鼠的咪喹莫特诱导的银屑病。我们的研究为银屑病的治疗提供了一种有效的策略。
