{"doi":"10.3389/fimmu.2022.1075804","title":"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.","journal":"Frontiers in Immunology","year":2023,"id":319843,"datarank":1.3354664487365304,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":0.7399226617037121,"self_endowment_contribution":0.5955437870328184,"citer_contribution":0.7399226617037121,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":52,"citers_with_citation_signal":40,"citers_with_endowment":40,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":990482,"name":"Sergette Banang‐Mbeumi","orcid":null,"position":1,"is_corresponding":false},{"id":990143,"name":"Samuel Boateng","orcid":"0000-0002-0307-3286","position":2,"is_corresponding":false},{"id":693245,"name":"Emmanuelle Ruiz","orcid":null,"position":3,"is_corresponding":false},{"id":990483,"name":"Roxane‐Cherille N. Chamcheu","orcid":null,"position":4,"is_corresponding":false},{"id":794374,"name":"Lin‐Woo Kang","orcid":"0000-0002-1411-3132","position":5,"is_corresponding":false},{"id":344645,"name":"Judy A. King","orcid":"0000-0001-9276-4275","position":6,"is_corresponding":false},{"id":794097,"name":"Anthony L. Walker","orcid":"0000-0001-7552-5192","position":7,"is_corresponding":false},{"id":417558,"name":"Bolni Marius Nagalo","orcid":"0000-0002-2173-7912","position":8,"is_corresponding":false},{"id":507028,"name":"Konstantin G. Kousoulas","orcid":"0000-0001-7077-9003","position":9,"is_corresponding":false},{"id":110406,"name":"Stéphane Esnault","orcid":"0000-0001-7238-8671","position":10,"is_corresponding":false},{"id":326807,"name":"Shile Huang","orcid":"0000-0002-3239-1072","position":11,"is_corresponding":false},{"id":373502,"name":"Jean Christopher Chamcheu","orcid":"0000-0002-3927-5664","position":12,"is_corresponding":false},{"id":407624,"name":"Tithi Roy","orcid":"0000-0003-3101-7705","position":0,"is_corresponding":true}],"reference_count":148,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:07:17.361058Z","pmid":"36741386","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}