Luteolin-7-glucoside inhibits IL-22/STAT3 pathway, reducing proliferation, acanthosis, and inflammation in keratinocytes and in mouse psoriatic model

Abstract

The epidermis is a dynamic tissue in which keratinocytes proliferate in the basal layer and undergo a tightly controlled differentiation while moving into the suprabasal layers. The balance between keratinocyte proliferation, differentiation, and death is essential, and its perturbation can result in pathological changes. Some common skin diseases, such as psoriasis, are characterized by hyperproliferation accompanied by inflammatory reactions, suggesting that molecules with topical anti-inflammatory and ROS scavenging abilities may be useful for their treatment. Here we investigate the potential of the flavone Luteolin-7-glucoside (LUT-7G) as a treatment for psoriasis. We show that LUT-7G leads to a modification of the cell cycle and the induction of keratinocyte differentiation, with modification of energy, fatty acid, and redox metabolism. LUT-7G treatment also neutralizes the proliferative stimulus induced by the proinflammatory cytokines IL-22 and IL-6 in HEKn. Moreover, in the Imiquimod (IMQ) mouse model of psoriasis, topical administration of LUT-7G leads to a marked reduction of acanthosis and re-expression of epidermal differentiation markers. Dissection of the IL-22 signalling pathway, activated by IMQ treatment, demonstrates that LUT-7G impairs the nuclear translocation of phosphorylated (activated) STAT3, blocking the IL-22 signalling cascade. Thus LUT-7G appears to be a promising compound for the treatment of hyperproliferative and inflammatory skin diseases, such as psoriasis.

Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2

“…Whereas control mice received a control cream (Vaseline; Walgreens Pharmacy), IMQ-treated mice received on the shaved back skin a daily topical dose of 50 mg of 5% IMQ cream (Aldara, Meda AB, Solna, Sweden). On day 5, skin biopsies of the treated area were collected with a 8-mm biopsy puncher, as previously described (Palombo et al, 2016). Epidermal and scale thickness, and cell infiltrate number were analysed as parameters of skin acanthosis and inflammation (not shown).…”

Effects of nanoparticles with hydrotropic nicotinamide on tacrolimus: permeability through psoriatic skin and antipsoriatic and antiproliferative activities

“…46 Inhibition of epidermal cell proliferation is very important in the treatment of psoriasis. To evaluate the inhibiting effect of different formulations on HaCaT cell proliferation, cell viability was measured with time.…”

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

“…Through activation of IL-36R, also IL-36γ directly induces EC proliferation, even though at a lower extent than IL-17A, possibly activating NF-κB and ERK1/2 signaling. The stronger activation of ERK1/2 and STAT3 pathways by IL-17A compared to that obtained with IL-36γ could explain the more pronounced mitogenic effect of IL-17A [26,36,37].…”

“…Human keratinocytes were obtained from skin biopsies of healthy donors as previously described [26]. Experiments were carried out on secondary and tertiary cultures and repeated at least three times on different strains.…”