A new approach for treatment of psoriasis: identification of galectin-7 as a novel regulator of inflammation in psoriasis.
Academia Sinica Vice President Dr. Fu-Tong Liu is a pioneer and leader in the field of galectin research. Not only was he the discoverer of now well-known galectin-3, he also found that different galectins play very important functions in different diseases, and different galectins have the potential to become targets for the treatment of different diseases. Dr. Hung-Lin Chen, a research technical contract-based employee from the Institute of Biomedical Sciences (IBMS), Academia Sinica, together with other researchers in the laboratory, and collaborators from IBMS and different institutions, under the leadership of Vice President Liu, reported the mechanism of galectin-7 in the inflammatory process of psoriasis. We also found that fluvastatin is an inducer of galectin-7 expression and can effectively inhibit the skin inflammation in a mouse model of psoriasis. The results were published in a prestigious international journal, The Journal of Clinical Investigation.
Psoriasis is a complex inflammatory skin disease where both genetic and environmental factors participate in its pathogenesis. Prominent characteristics of this disease include keratinocyte hyperproliferation and leukocyte infiltration in the lesional skin. Although the etiology is not clear, hyperactive keratinocytes and immune cells are key players in the pathogenesis of psoriasis, and the cross-talk between these cells contributes to the pathological phenotype. Moreover, psoriasis is considered as a metabolic syndrome, associated with dyslipidemia and an increased risk of cardiovascular disease.
Galectin-7, a 15 kDa β-galactoside–binding protein, is highly expressed in epidermal keratinocytes and is induced by the tumor suppressor p53. Galectin-7 is primarily an intracellular protein and can be located both in the nucleus and cytoplasm of keratinocytes, although it also exists outside the cell and is capable of binding to various glycoconjugates in the extracellular space. Downregulation and nuclear translocation of galectin-7 in transformed and ultraviolet-light–irradiated keratinocytes have been reported, suggesting that galectin-7 may participate in cellular homeostasis. In mice, galectin-7 was reported to regulate skin homeostasis during injury, but the detailed mechanism is not clear. Previously, we have investigated the role of galectin-7 in the regulation of keratinocyte proliferation, but how galectin-7 functions in keratinocytes in the inflammatory response occurring in human inflammatory skin diseases, such as psoriasis, is not clear.
In the data obtained in our previous transcriptomic study, we found that galectin-7 mRNA is downregulated in the skin lesions of patients with psoriasis). In the present study, we first explored the protein levels of galectin-7 in psoriasis and then investigated whether its downregulation in the epidermis of psoriatic lesions contributes to the inflammatory response and epidermal hyperplasia associated with psoriasis.
To examine galectin-7 protein expression in human skin lesions, we performed immunohistochemistry analysis using skin samples from a cohort of patients with psoriasis and normal skin from healthy controls. We found that galectin-7 expression is downregulated in human psoriatic lesions and mouse psoriasiform dermatitic lesions induced by IL-23.
By microarray analysis, deep sequencing, and real-time PCR analyses, we have previously found that miR-146a was upregulated in galectin-7 knockdown HaCaT cells. We showed miR-146a was similarly significantly overexpressed in HEKn cells with a transient galectin-7 knockdown. In this study, we demonstrated that miR-146a can promote production of inflammatory mediators by keratinocytes through the MAPK-ERK pathway. Microarray analysis of galectin-7 knockdown HaCaT cells revealed upregulation of several chemokine genes (CCL3, CCL4, CXCL2, CXCL3, and others) and psoriasis-related genes (including serine protease inhibitors, SERPINA3 and SERPINB4; S100 calcium-binding proteins, S100A7 and S100A7A; and defensin β4A, DEFB4A) in these cells, as compared with control cells (our unpublished observations). This finding suggested that reduced galectin-7 expression might promote inflammation, thereby contributing to the pathogenesis of psoriasis. To further assess the participation of galectin-7 in the regulation of inflammatory responses in vivo, we studied galectin-7–deficient mice to determine the role of galectin-7 in IL-23–induced skin inflammation. We found that galectin-7–deficient mice exhibited enhanced epidermal hyperplasia and skin inflammation in response to intradermal IL-23 injection.
To examine the expression of galectin-7 in the skin during IL-23-induced inflammatory response in vivo, we generated a galectin-7-EGFP fusion transgenic mouse model. Live deep-tissue visualization of galectin-7 expression in EGFP-galectin-7 transgenic mice by two-photon microscopy was performed. In the three-dimensional images we obtained, the green fluorescence signal was found to be confined only to keratinocytes and hair follicles in the skin.
To utilize our observations on the anti-inflammatory and antiproliferative effects of galectin-7, we scrutinized microarray databases for approved drugs that can induce galectin-7 expression. We identified fluvastatin as an inducer of galectin-7 expression by connectivity map (cMAP) analysis, confirmed this effect in keratinocytes, and demonstrated that fluvastatin attenuated IL-6 and IL-8 production induced by IL-17A. Thus, we validated a role of galectin-7 in the pathogenesis of psoriasis, in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses, and formulated a rationale for the use of statins in the treatment of psoriasis.
Galectin-7 expression in keratinocytes is downregulated by cytokines responsible for the development of psoriasis. This results in hyperproliferation of keratinocytes and skin inflammation. Approaches to induce galectin-7 in keratinocytes may be useful for the treatment of psoriasis. We have identified one such approach: the use of selected kinds of statins, which is intriguing, as psoriasis is considered a metabolic syndrome associated with dyslipidemia, and thus patients would benefit from the use of statins. Additional investigations along this approach have the potential to identify statins that are selected on the basis of their potency in the induction of galectin-7 and thus more effective in the treatment of psoriasis.