Dual targeting of mTOR/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation

Abstract

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.

Pivotal Role of mTOR in Non-Skin Manifestations of Psoriasis

“…The mTOR activation in epithelial cells and resident macrophages in the skin and other psoriasis-affected tissues stimulate the production of IL-17, which also stimulates the production of IL-12 and IL-23, activating the endothelial and resident immune cells to produce TNF-α. With the higher levels of TNF-α [ 25 ], both vascular and skin tissues recruit TH17 T lymphocytes, which produce higher levels of IL-17 [ 25 ].…”

Galgravin Isolated from Piper kadsura Ameliorates Lipopolysaccharide (LPS)-Induced Endotoxemia in Mice

“…The collected chloroform fraction was concentrated to dry powder (350 g) and then subjected to silica gel column chromatography (10 × 120 cm) with a gradient solvent constituted by ethyl acetate in n-hexane (0-100%) to obtain 14 fractions (No. [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. A solid precipitate was separated from fraction 7 and recrystallized from methanol to provide galgravin (3.5 g), which was then stored at −20 • C. The purity of galgravin was assessed using the HPLC method.…”

“…Many natural products with anti-inflammatory activity have been identified from medicinal plants, such as andrographolide [7,8], curcumin [9], fisetin [10], gossypol [11], and lycorine [12], suggesting that herbal medicine has therapeutic potential for treating sepsis [13]. Piper kadsura is a vine-like plant in southeast China and Taiwan [14][15][16], whereas its stem is widely used as a folk medicine for the treatment of rheumatoid arthritis, gouty arthritis, asthma, and cerebral ischemia [14].…”

MATN3 delivered by exosome from synovial mesenchymal stem cells relieves knee osteoarthritis: Evidence from in vitro and in vivo studies

“…The downregulation of ciRS-7 or upregulation of miR-7 exacerbates cartilage degradation and autophagy defects in IL-17A-mediated PI3K/AKT/mTOR activation in OA [ 35 ]. Nonivamide effectively inhibits the IL-17A and Akt/mTOR pathways, promotes keratinocyte differentiation, activates autophagy, and relieves imiquimod-induced psoriasis-like diseases in mice [ 36 ]. Notably, IL-17A is involved in the progression of OA, which can activate the PI3K/AKT/mTOR pathway to affect cartilage degradation and autophagy defection [ 35 ].…”