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 the skin lesions of patients with psoriasis. IL-17A and TNFα, two 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-17Ainduced production of inflammatory mediators by keratinocytes via the miR-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 (cMAP) 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 formulated a rationale for the use of statins in the treatment of psoriasis.

Increased Circulating Levels of Galectin Proteins in Patients with Breast, Colon, and Lung Cancer

“…Galectin-7 is highly expressed in epithelial tissues, especially stratified squamous epithelium, which corroborates this finding [ 38 ]. Galectin-7 was found to play a role in the pathogenesis of psoriasis, an inflammatory process affecting stratified squamous cells of the skin by elevating levels of IL-6 and IL-8 [ 39 ]. The elevated serum levels of galectin-7 in patients with tumors of squamous cell origin help to explain the origin of galectins in the serum.…”

Medawar’s PostEra: Galectins Emerged as Key Players During Fetal-Maternal Glycoimmune Adaptation

“…Gal-7 production is regulated by p53, TNF-α and NFĸB ( 97 ), but based on upstream promotor region sequencing it is predicted that LGALS7 and LGALS7B may each be regulated by different transcription factors ( 97 , 99 , 107 ). Studies to date suggest that gal-7 has key functions in epithelial cell homeostasis, including cell growth, differentiation and apoptosis as well as functions in cell adhesion, migration and immune cell regulation ( 101 , 108 ; 97 , 105 , 106 , 109 – 116 ).…”

“…In vivo administration of exogenous gal-7 to pregnant mice during mid-gestation results in a pro-inflammatory response with elevated placental IL-1 β and IL-6 and reduced IL-10 mRNA production ( 120 ). Other reports however, indicate that gal-7 has anti-inflammatory actions treatment of PMA-stimulated Jurkat cells with gal-7 inhibits IL-2 and INF-γ production ( 112 ), gal-7 silencing elevates IL-17A-stimulated HaCaT cell secretion of IL-6 and IL-18 ( 107 ) and gal-7 is down-regulated in a mouse model of psoriasis ( 107 ). Therefore, the immune regulatory role of gal-7 may be cell-type specific and/or may depend on its cellular localization.…”

Functions and Inhibition of Galectin-7, an Emerging Target in Cellular Pathophysiology

“…More recently, it was found that the expression of galectin-7 is reduced by cytokines in the skin lesions of patients with psoriasis. This results in the hyperproliferation of keratinocytes and skin inflammation [ 20 ].…”