期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 145, 期 1, 页码 199-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.09.025
关键词
L-type amino acid transporter 1; SLC7A5; psoriasis; gamma delta T cells; T(H)17; mammalian target of rapamycin
资金
- Spanish Ministry of Economy and Competitiveness [SAF 2017-82886-R, PI17/01972, SAF 2013-42850-R]
- Comunidad de Madrid [S2017/BMD-3671-INFLAMUNE-CM]
- CIBERCV
- Instituto de Salud Carlos III [BIOIMID PIE13/041]
- Fundacion La Marato TV3 [20152330 31]
- FUNDACION BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA 2018
- la Caixa'' Banking Foundation [HR17-00016]
- Agencia Estatal de Investigacion, Fondo Europeo de Desarrollo Regional, European Union
Background: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1 beta, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored. Objective: We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis. Methods: LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor-related orphan receptor gamma. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH2O3) and mammalian target of rapamycin (mTOR [rapamycin]). Results: LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in gamma delta and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17-secreting gamma 4(+)delta 4(+) and CD4 T cells and dampens the release of IL-1 beta, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human gamma delta T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1 beta stimulation upregulates LAT1 expression and induces mTOR activation in IL-17 + gamma delta and T(H)17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23- and IL-1 beta-induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling. Conclusion: Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to control skin inflammation mediated by the IL-23/IL-1 beta/IL-17 axis.
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