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 2

Downregulation of galectin-7 in keratinocytes causes an elevated production of the proinflammatory cytokines IL-6 and IL-8 in response to IL-17A stimulation.

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Downregulation of galectin-7 in keratinocytes causes an elevated product...
(A and B) Galectin-7–knockdown HaCaT cell lines (sh-1, sh-2, sh-3, and sh-4) and controls were incubated with or without IL-17A for 2 days, and IL-6 and IL-8 concentrations in the supernatants were measured by ELISA. All the experiments included 3 biological replicates. (C and D) HEKn cells were transfected with siRNA to knock down galectin-7 and then incubated with or without IL-17A for 2 days. The IL-6 and IL-8 concentrations in the supernatants were measured by ELISA. Three independent biological replicates were performed for the ELISA analysis. The results are presented as mean ± SD. For statistical analysis, 2-way ANOVA with Tukey’s multiple-comparison test was performed. Each shRNA- or siRNA-treated cell line was compared with its corresponding control (V, vector; si-NC, negative control siRNA) for both untreated and IL-17–treated groups. The shRNAs and siRNAs for the knockdown of galectin-7 expression were as described in Methods. *P < 0.05, **P < 0.01.