The Skin-Liver Axis Modulates the Psoriasiform Phenotype and Involves Leucine-Rich α-2 Glycoprotein
The Skin-Liver Axis Modulates the Psoriasiform Phenotype and Involves Leucine-Rich α-2 Glycoprotein
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DOI：
10.4049/jimmunol.2000502
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发表时间：
2021-04-01
影响因子：
4.4
通讯作者：
Sano, Shigetoshi
中科院分区：
文献类型：
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作者：
Nakajima, Hideki;Nakajima, Kimiko;Sano, Shigetoshi
富含亮氨酸的α2糖蛋白（LRG）是主要由肝脏产生的急性期蛋白之一，与C反应蛋白类似，已被认为是类风湿性关节炎和炎症性肠病的炎症生物标志物。我们最近证明，LRG 在银屑病患者的血清中也有所增加，并且与疾病活动性密切相关，其敏感性和特异性远高于 C 反应蛋白；然而，LRG 是否在机制上促进银屑病的发病机制仍不清楚。在这项研究中，我们使用 LRG 敲除 (KO) 小鼠在咪喹莫特 (IMQ) 介导的模型中探讨了 LRG 在银屑病炎症中的作用。 IMQ 局部治疗后，LRG 的血清水平及其在肝脏中的表达突然升高。同样，尽管 LRG-KO 小鼠表现出延迟的反应，但在肝脏中观察到促炎细胞因子的急剧激增，包括 IL-1β、TNF-α 和 IL-6。 LRG-KO 小鼠在 IMQ 模型中表现出比野生型小鼠更少的皮肤炎症。 K5.Stat3C 小鼠在剥离胶带后出现银屑病样病变，这也突然诱导肝脏中 LRG 表达。 Lrg 的缺乏减轻了胶带剥离引起的损伤，类似于 IMQ 模型。这些结果表明 LRG 调节与银屑病炎症有关的皮肤-肝脏轴中细胞因子的前馈和反馈环路。
Leucine-rich alpha-2 glycoprotein (LRG), one of the acute phase proteins mainly produced by the liver, similar to C-reactive protein, has been recognized as an inflammatory biomarker for rheumatoid arthritis and inflammatory bowel diseases. We recently demonstrated that LRG was also increased in the sera of psoriasis patients and correlated well with disease activity with a sensitivity and specificity much higher than C-reactive protein; however, whether LRG mechanistically contributed to the pathogenesis of psoriasis remained unclear. In this study, we explored the role of LRG in psoriasiform inflammation using LRG-knockout (KO) mice in an imiquimod (IMQ)-mediated model. Following topical treatment with IMQ, serum levels of LRG and its expression in the liver were abruptly elevated. Similarly, an acute surge of proinflammatory cytokines was observed in the liver, including IL-1 beta, TNF-alpha, and IL-6, although LRG-KO mice showed delayed responses. LRG-KO mice showed less skin inflammation in the IMQ model than wild-type mice. K5.Stat3C mice developed psoriasis-like lesions following tape stripping, which also abruptly induced LRG expression in the liver. A deficiency of Lrg mitigated tape stripping-induced lesions, similar to the IMQ model. These results indicate that LRG modulates both feed-forward and feedback loops of cytokines in the skin-liver axis involved with psoriasiform inflammation.