Abstract
Psoriasis is a chronic inflammatory skin disease marked by aberrant tissue repair. Mutant mice modeling psoriasis skin characteristics have provided useful information relevant to molecular mechanisms and could serve to evaluate therapeutic strategies. Here, we found that epidermal ANGPTL6 expression was markedly induced during tissue repair in mice. Analysis of mice overexpressing ANGPTL6 in keratinocytes (K14-Angptl6 Tg mice) revealed that epidermal ANGPTL6 activity promotes aberrant epidermal barrier function due to hyperproliferation of prematurely differentiated keratinocytes. Moreover, skin tissues of K14-Angptl6 Tg mice showed aberrantly activated skin tissue inflammation seen in psoriasis. Levels of the proteins S100A9, recently proposed as therapeutic targets for psoriasis, also increased in skin tissue of K14-Angptl6 Tg mice, but psoriasis-like inflammatory phenotypes in those mice were not rescued by S100A9 deletion. This finding suggests that decreasing S100A9 levels may not ameliorate all cases of psoriasis and that diverse mechanisms underlie the condition. Finally, we observed enhanced levels of epidermal ANGPTL6 in tissue specimens from some psoriasis patients. We conclude that the K14-Angptl6 Tg mouse is useful to investigate psoriasis pathogenesis and for preclinical testing of new therapeutics. Our study also suggests that ANGPTL6 activation in keratinocytes enhances psoriasis susceptibility.
Highlights
Biological agents were developed as therapeutics for psoriasis
We found that ANGPTL6 overexpression in keratinocytes of transgenic (K14-Angptl[6] Tg) mice promotes thickened epidermis marked by hyper-proliferation of prematurely differentiated keratinocytes and increased chemokine/cytokine expression, accelerating recruitment of neutrophils and endothelial cells to epidermis and contributing to phenotypic changes associated with psoriasis
Epidermal water barrier function is disrupted in the active phase of psoriasis[19,20]; we examined related phenotypes in skin tissue of K14-Angptl[6] Tg mice by estimating transepidermal water loss (TEWL)
Summary
Biological agents were developed as therapeutics for psoriasis. As anticipated, these agents are more effective than conventional therapies[3,8] but can induce side effects associated with immune suppression, restricting their application[8]. Skin tissues of JunB/c-Jun double-mutant (DKO) mice show elevated levels of S100A9 proteins, and in humans genes encoding these proteins are localized in the psoriasis susceptibility region PSORS410. Psoriasis-like skin proliferative and inflammatory phenotypes are significantly rescued in DKO mice in which S100A9 is genetically deleted[11], suggesting that S100A9 could be a useful therapeutic target for psoriasis. ANGPTL6, known as Angiopoietin-related growth factor (AGF), functions in proliferation of epidermal keratinocytes and in remodeling, repair and regeneration of skin tissue in mice[13]. The human ANGPTL6 gene is located at 19p13.2 in a region known as the psoriasis susceptibility region PSORS614,15. These findings suggest a potential role for ANGPTL6 in psoriasis susceptibility, this associated has not been documented. To the best of our knowledge, this is the first report showing that increased ANGPTL6 activity in keratinocytes may enhance psoriasis susceptibility
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