Zhang Jie, Shu Jie, Sun Hanxiao, Zhai Tianhang, Li Huidan, Li Haichuan, Sun Yue, Huo Rongfen, Shen Baihua, Sheng Huiming
Department of Clinical Laboratory of Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Dermatol. 2023 Mar;50(3):337-348. doi: 10.1111/1346-8138.16611. Epub 2022 Nov 14.
Psoriasis is a chronic skin disorder characterized by epidermal keratinocyte hyperproliferation and inflammatory infiltration. CCN1 (also termed CYR61 or cysteine-rich angiogenic inducer 61) is an extracellular matrix-associated protein that is involved in multiple physiological functions. In psoriasis, we recently demonstrated that the overexpression of CCN1 promoted keratinocyte proliferation and activation. Furthermore, CCN1 was highly expressed in psoriatic skin lesions from psoriasis vulgaris patients. Here, we dissect the underlying molecular mechanism in imiquimod (IMQ) and interleukin (IL)-23-induced psoriasis-like models. Our results demonstrate that CCN1 can significantly upregulate IL-36 production in the murine skin of IMQ and IL-23-induced psoriasis-like models. Injection of CCN1-neutralizing antibody improved epidermal acanthosis and significantly reduced IL-36 production in vivo. These results suggest that CCN1 can be a critical upstream pro-inflammatory factor in psoriasis. In primary normal human epidermal keratinocytes, we demonstrated that CCN1 can selectively induced the production of IL-36α and IL-36γ through the activation of the protein kinase B (AKT)/nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and extracellular-regulated kinase (ERK)/CCAAT/enhancer binding protein β (CEBPβ) signaling pathways via integrin receptor α6β1 in vitro. Our results suggest that targeting CCN1 can be a potential therapeutic strategy for psoriasis.
银屑病是一种慢性皮肤疾病，其特征为表皮角质形成细胞过度增殖和炎症浸润。CCN1（也称为CYR61或富含半胱氨酸的血管生成诱导因子61）是一种与细胞外基质相关的蛋白质，参与多种生理功能。在银屑病中，我们最近证明CCN1的过表达促进角质形成细胞的增殖和活化。此外，CCN1在寻常型银屑病患者的银屑病皮肤病变中高表达。在此，我们剖析咪喹莫特（IMQ）和白细胞介素（IL）-23诱导的银屑病样模型中的潜在分子机制。我们的结果表明，在IMQ和IL-23诱导的银屑病样模型的小鼠皮肤中，CCN1可显著上调IL-36的产生。注射CCN1中和抗体可改善表皮棘皮症，并在体内显著降低IL-36的产生。这些结果表明，CCN1可能是银屑病中关键的上游促炎因子。在原代正常人表皮角质形成细胞中，我们证明CCN1在体外可通过整合素受体α6β1激活蛋白激酶B（AKT）/活化B细胞核因子κB轻链增强子（NF-κB）和细胞外调节激酶（ERK）/CCAAT/增强子结合蛋白β（CEBPβ）信号通路，选择性诱导IL-36α和IL-36γ的产生。我们的结果表明，靶向CCN1可能是银屑病的一种潜在治疗策略。
