Huidan Li1, Haichuan Li2, Rongfen Huo1, Pinru Wu3, Zhengyu Shen3, Hui Xu3, Baihua Shen1, Ningli Li4. 1. Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Maternity and Child Health Hospital, Changning, Shanghai, China. 3. Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 4. Shanghai Institute of Immunology & Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: ninglixiaoxue57@163.com.
Abstract
BACKGROUND: Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has recently been implicated in psoriasis pathogenesis by promoting keratinocyte activation. However, the mechanisms by which CCN1 enhances cutaneous inflammation are not fully understood. OBJECTIVE: In this study, we investigated the role of CCN1 on the expression of CCL20 in human keratinocyte. METHODS AND RESULTS: By double-label immunofluorescence staining, we first identified that the expression of CCN1 colocalized well with CCL20 production in the epidermis of psoriasis skin lesion. Furthermore, in vivo, blocking or knockdown CCN1 expression ameliorated skin inflammation and reduced the expression of CCL20 in both imiquimod and IL-23-induced psoriasis-like mouse models, which indicated that CCN1 might be involved in the regulation of CCL20 production in psoriasis. Next, in vitro, we stimulated primary normal human epidermal keratinocyte (NHEK) with exogenous protein CCN1 and found that CCN1 directly upregulated CCL20 production independent of TNF-α, IL-22 and IL-17 pathway. Lastly, the signaling pathway study showed that CCN1 enhanced the binding of AP-1 to the CCL20 promoter via crosstalk with p38 and JNK. CONCLUSIONS: Our study demonstrates that CCN1 stimulates CCL20 production in vitro and in vivo, and thus supports the notion that overexpressed CCN1 in hyperproliferating keratinocyte is functionally involved in the recruitment of inflammatory cells to skin lesions affected by psoriasis.
BACKGROUND:Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has recently been implicated in psoriasis pathogenesis by promoting keratinocyte activation. However, the mechanisms by which CCN1 enhances cutaneous inflammation are not fully understood. OBJECTIVE: In this study, we investigated the role of CCN1 on the expression of CCL20 in human keratinocyte. METHODS AND RESULTS: By double-label immunofluorescence staining, we first identified that the expression of CCN1 colocalized well with CCL20 production in the epidermis of psoriasis skin lesion. Furthermore, in vivo, blocking or knockdown CCN1 expression ameliorated skin inflammation and reduced the expression of CCL20 in both imiquimod and IL-23-induced psoriasis-like mouse models, which indicated that CCN1 might be involved in the regulation of CCL20 production in psoriasis. Next, in vitro, we stimulated primary normal human epidermal keratinocyte (NHEK) with exogenous protein CCN1 and found that CCN1 directly upregulated CCL20 production independent of TNF-α, IL-22 and IL-17 pathway. Lastly, the signaling pathway study showed that CCN1 enhanced the binding of AP-1 to the CCL20 promoter via crosstalk with p38 and JNK. CONCLUSIONS: Our study demonstrates that CCN1 stimulates CCL20 production in vitro and in vivo, and thus supports the notion that overexpressed CCN1 in hyperproliferating keratinocyte is functionally involved in the recruitment of inflammatory cells to skin lesions affected by psoriasis.
Authors: Yong Liu; Sheng Nan Cui; Meng Yao Duan; Zhi Li Dou; Yi Zhen Li; Yi Xing Liu; Ye Xia; Jia Wei Zhang; Xiao Ning Yan; Dong Ran Han Journal: Virol J Date: 2021-07-02 Impact factor: 4.099