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 3

MiR-146a is upregulated in the epidermis of psoriatic lesions; this miRNA promotes production of the proinflammatory cytokines IL-6 and IL-8.

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MiR-146a is upregulated in the epidermis of psoriatic lesions; this miRN...
(A) MiR-146a in the epidermis of normal and psoriatic skin was detected by RNA in situ hybridization assay. Scale bars: 100 μm. (B) The miR-146a level in HaCaT cells treated with IL-17A was quantified by real-time PCR. (C and D) A miR-146a–overexpressing vector (pmiR-146a) and a scrambled control hairpin in pCDH-CMV-MCS-EF1-copGFP (pmiR) from SBI (System Biosciences) were used to generate stable miR-146a–overexpressing and control cell clones, respectively. The secretion of cytokines (IL-6 and IL-8) by HaCaT cells stably transfected with pmiR or pmiR-146a vectors was measured 2 days after stimulation with 25 or 100 ng/mL IL-17A. Three independent biological replicates were performed for the real-time PCR analysis. All results are presented as mean ± SD. For statistical analysis, unpaired Student’s t test (B) or 2-way ANOVA with Tukey’s multiple-comparison test (C and D) was performed. **P < 0.01, ***P < 0.001.