Galectin-7 downregulation in lesional keratinocytes contributes to enhanced IL-17A signaling and skin pathology in psoriasis
Hung-Lin Chen, … , Daniel K. Hsu, Fu-Tong Liu
Hung-Lin Chen, … , Daniel K. Hsu, Fu-Tong Liu
Published October 15, 2020
Citation Information: J Clin Invest. 2021;131(1):e130740. https://doi.org/10.1172/JCI130740.
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Research Article Autoimmunity Dermatology

Galectin-7 downregulation in lesional keratinocytes contributes to enhanced IL-17A signaling and skin pathology in psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration, as well as hyperproliferation of keratinocytes in skin lesions, and is considered a metabolic syndrome. We found that the expression of galectin-7 is reduced in skin lesions of patients with psoriasis. IL-17A and TNF-α, 2 cytokines intimately involved in the development of psoriatic lesions, suppressed galectin-7 expression in human primary keratinocytes (HEKn cells) and the immortalized human keratinocyte cell line HaCaT. A galectin-7 knockdown in these cells elevated the production of IL-6 and IL-8 and enhanced ERK signaling when the cells were stimulated with IL-17A. Galectin-7 attenuated IL-17A–induced production of inflammatory mediators by keratinocytes via the microRNA-146a/ERK pathway. Moreover, galectin-7–deficient mice showed enhanced epidermal hyperplasia and skin inflammation in response to intradermal IL-23 injection. We identified fluvastatin as an inducer of galectin-7 expression by connectivity map analysis, confirmed this effect in keratinocytes, and demonstrated that fluvastatin attenuated IL-6 and IL-8 production induced by IL-17A. Thus, we validate a role of galectin-7 in the pathogenesis of psoriasis, in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses, and formulate a rationale for the use of statins in the treatment of psoriasis.

Authors

Hung-Lin Chen, Chia-Hui Lo, Chi-Chun Huang, Meng-Ping Lu, Po-Yuan Hu, Chang-Shan Chen, Di-Yen Chueh, Peilin Chen, Teng-Nan Lin, Yuan-Hsin Lo, Yu-Ping Hsiao, Daniel K. Hsu, Fu-Tong Liu

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Figure 4

Reduced galectin-7 expression and miR-146a overexpression promote ERK1 and ERK2 signaling pathways triggered by IL-17A.

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Reduced galectin-7 expression and miR-146a overexpression promote ERK1 a...
(A) Galectin-7–knockdown HaCaT cells and control cells were treated with IL-17A for 5 minutes, and cell lysates were analyzed by immunoblotting. Total ERK1, ERK2, NF-κB, and IκBα and their phosphorylated forms were detected with the corresponding antibodies. (B) HaCaT cells stably transfected with pmiR (control vector) or pmiR-146a were treated with IL-17A for 5 minutes. Immunoblotting was performed as described in A. Protein quantification data on phospho-ERK1 (p-ERK1) and phospho-ERK2 (p-ERK2) were normalized to the control group in A and the miR group in B. Data on total protein levels, levels of phosphorylated NF-κB and IκBα, and total protein levels of ERK1 and ERK2 were normalized to the control (0 minutes).