Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation

Autor: Francisco Sánchez-Madrid, Julián Aragonés, María Laura Saiz, Jesús Vázquez, Hortensia de la Fuente, Esteban Daudén, Inmaculada Jorge, Danay Cibrian, Manuel Fresno, Javier Fraga-Fernández, Marta Ramírez-Huesca, Raquel Castillo-González, Miguel Vicente-Manzanares, Nieves Fernández-Gallego, Carmen Punzón
Přispěvatelé: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Instituto de Salud Carlos III, Fundació La Marató de TV3, Fundación BBVA, Fundación 'la Caixa', European Commission, UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-IP), Comunidad de Madrid (España), Fundación La Marató TV3, Fundación La Caixa, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Medicina
Immunology
Retinoic acid
Inflammation
Mice
Transgenic
Adaptive Immunity
SLC7A5
γδ T cells
Large Neutral Amino Acid-Transporter 1
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
RAR-related orphan receptor gamma
Psoriasis
medicine
Immunology and Allergy
Animals
Humans
Amino acid transporter
PI3K/AKT/mTOR pathway
Skin
mammalian target of rapamycin
chemistry.chemical_classification
Orphan receptor
Mammalian target of rapamycin
integumentary system
L-type amino acid transporter 1
T(H)17
Amino Acid Transport System y+L
psoriasis
T 17 H
medicine.disease
Immunity
Innate
Amino acid
Disease Models
Animal
030104 developmental biology
chemistry
Gene Expression Regulation
Cancer research
Cytokines
Th17 Cells
medicine.symptom
030215 immunology
Signal Transduction
Zdroj: Biblos-e Archivo: Repositorio Institucional de la UAM
Universidad Autónoma de Madrid
Digital.CSIC. Repositorio Institucional del CSIC
instname
Repisalud
Instituto de Salud Carlos III (ISCIII)
Biblos-e Archivo. Repositorio Institucional de la UAM
Popis: [Background]: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1β, 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 γ. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH203) 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 γδ and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17–secreting γ4+δ4+ and CD4 T cells and dampens the release of IL-1β, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human γδ T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1β stimulation upregulates LAT1 expression and induces mTOR activation in IL-17+ γδ and TH17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23– and IL-1β–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-1β/IL-17 axis.
Supported by grants SAF2017-82886-R (to F.S.-M.), PI17/01972 (to E.D.), and SAF2013-42850-R (to M.F.) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD-3671-INFLAMUNE-CM) from the Comunidad de Madrid (to F.S.-M.); and CIBERCV, BIOIMID PIE13/041 from Instituto de Salud Carlos III and Fundacion La Marato TV3 (20152330 31). The project leading to these results has also received funding from FUNDACION BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA 2018 and from ‘‘la Caixa’’ Banking Foundation under the project code HR17-00016 (to F.S.-M.) and from Agencia Estatal de Investigacion, Fondo Europeo de Desarrollo Regional, European Union.
Databáze: OpenAIRE
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