Drug screening identifies the Src/Abl inhibitor Dasatinib as suppressor of IL-23 signalling in skin inflammation
Navarro, M. N.; Valle-Pastor, M. J.; Cayuela, I.; Yebra, J. S.; Senach-Rasilla, L.; Pastor-Fernandez, G.; Oliva, A.; Traba, J.
Show abstract
IL-23-driven IL-17 production by {gamma}{delta}17 and Th17 cells is central to the pathogenesis of psoriasis and other autoimmune disorders. The intracellular mechanisms linking IL-23 signalling to effector cytokine production remain incompletely defined and thus, therapeutic targets downstream of IL-23 are limited. Here, we developed an in vitro model based on a {gamma}{delta}17 T cell line to study IL-23 responses and identify pharmacological inhibitors of type 3 immunity. We conducted a drug-repurposing screening of FDA-approved compounds and identified Src/Abl kinase inhibitors Dasatinib and Bosutinib as potent suppressors of IL-23-induced IL-17A production. In vivo, intraperitoneal and topical Dasatinib administration reduced epidermal thickening, immune cell infiltration, and the accumulation of IL-17-producing T cells in the Imiquimod model of skin inflammation. Mechanistically, Dasatinib and Bosutinib blocked IL-23-dependent mTORC1 and mTORC2 activation. Finally, loss-of-function experiments identified the Src kinase Blk as a critical mediator of IL-23-induced mTORC1 activation and IL-17A production in {gamma}{delta}17 T cells. These findings uncover a novel IL-23-Src-mTOR axis in type 3 immunity, opening the door for therapeutic targeting of Src signalling networks in IL-23/IL-17-driven inflammation.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Layilin Regulates Treg Motility and Suppressive Capacity in Skin 95%
- Thymic dendritic cell-derived IL-27p28 promotes the establishment of functional bias against IFN-γ production in newly generated CD4+ T cells through STAT1-related epigenetic mechanisms 95%
- Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity 95%
Similar papers in this journal
Similar papers in this journal
- Type I interferons are important co-stimulatory signals during T cell receptor mediated MAIT cell activation 94%
- Vitamin A-treated NK cells reduce IFN-gamma production and support regulatory T cell differentiation 94%
- Fibroblastic reticular cells provide a supportive niche for lymph node-resident macrophages 94%
Similar papers in this journal
- The guanine nucleotide exchange factor Rin-like acts as a gatekeeper for T follicular helper cell differentiation via regulating CD28 signaling 95%
- Blimp-1 is essential for Th2 cell development and allergic asthma 94%
- Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signalling 93%
Similar papers in this journal
- Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling 96%
- PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade 94%
- An essential role for miR-15/16 in Treg suppression and restriction of proliferation 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.