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

Fluvastatin increases galectin-7 levels in keratinocytes, suppresses production of proinflammatory cytokines, and attenuates IL-23–induced epidermal thickness.

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Fluvastatin increases galectin-7 levels in keratinocytes, suppresses pro...
(A and B) Real-time PCR analysis of the mRNA expression of galectin-7 and S100A7 in HaCaT cells treated with methylprednisolone (10.6 μM), tobramycin (8.6 μM), fluvastatin (9.2 μM), pempidine (13 μM), or vehicle control (DMSO) for 24 hours. The relative fold changes were calculated using the ΔΔCt method; data from all the samples were normalized to the control sample, and GAPDH served as an endogenous control. (C and D) Production of IL-6 and IL-8 by HaCaT cells treated for 2 days with fluvastatin with or without IL-17A (200 ng/mL) was measured by ELISA. For statistical analysis, each group was compared with control group (first bar: group without IL-17A, DMSO, and fluvastatin). (E) Immunoblotting analysis of galectin-7 in keratinocytes treated with TNF-α or IL-17A with or without fluvastatin or DMSO. (F) Ear thicknesses of different groups — PBS (n = 3), IL-23 (n = 3), PBS + vehicle (n = 5), IL-23 + vehicle (n = 5), PBS + fluvastatin (n = 3), IL-23 + fluvastatin (n = 5), PBS + pravastatin (n = 4), IL-23 + pravastatin (n = 5) — of mice subjected to intradermal injections of IL-23 or PBS, as described in Figure 5, and treated with fluvastatin (blue line), pravastatin (green line), or saline. For statistical analysis, either 1-way (A and B) or 2-way (C, D, and F) ANOVA with Tukey’s multiple-comparison test was used. Three independent biological replicates were performed for real-time PCR and ELISA analyses. The results (adjusted P values) of group pairs are annotated on the graph (IL-23 + fluvastatin group vs. corresponding IL-23 + vehicle group indicated in gray; IL-23 + fluvastatin group vs. corresponding IL-23 + pravastatin group indicated in green). *P < 0.05, **P < 0.01, ***P < 0.001.