Gal-1 and lat1 as regulatory molecules in skin inflammatory diseases
- Autores: Raquel Ana Castillo González
- Directores de la Tesis: Francisco Sánchez Madrid (dir. tes.), Danay Cibrián Vera (codir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
- Idioma: español
- Tribunal Calificador de la Tesis: Manuel Fresno Escudero (presid.), María José Calzada García (secret.), Esteban Daudén Tello (voc.), Balbino Jose Alarcon Sanchez (voc.), Miguel Vicente Manzanares (voc.)
- Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
Skin diseases are common disorders with a high prevalence among occupational diseases. Allergic contact dermatitis (ACD) and psoriasis are complex and frequent inflammatory skin pathologies in which the immune system and epithelial alterations play an important role in their development. ACD, also known as contact hypersensitivity (CHS), is a frequent T-cell mediated inflammatory skin disease characterized by red, itchy, swollen and cracked skin. It is caused by the direct contact with an allergen and/or irritant. Galectin-1 (Gal-1) is a β-galactoside-binding lectin which is highly expressed in several types of immune cells. The role of endogenous Gal-1 in CHS is not known. We found that Gal-1-deficient mice display more sustained and prolonged skin inflammation than wild-type mice after oxazolone treatment. Gal-1-deficient mice have increased CD8+ T cells and neutrophilic infiltration in the skin. After the sensitization phase, Gal-1-depleted mice showed increased frequency of central memory CD8+ T cells and IFNγ secretion by CD8+ T cells. The absence of Gal-1 does not affect migration of transferred CD4+ and CD8+ T cells from the blood to the lymph nodes or to the skin. Depletion of CD4+ T lymphocytes as well as adoptive transfer experiments demonstrated that endogenous expression of Gal-1 on CD8+ T lymphocytes exerts a major role in the control of CHS model. These data underscore the protective role of endogenous Gal-1 in CD8+ but not CD4+ T cells in the development of CHS disease.
Psoriasis is a common chronic skin disorder characterized by a thickened epidermis caused by keratinocyte (KC) proliferation and dermal inflammatory infiltrate. The main clinical manifestation is the presence of raised, squamous, erythematous oval plaques. The progress of this pathology can be affected by diverse causes such as immune system, genetic, autoantigens and environmental factors. It is mainly mediated by IL-23, IL-1β, and IL-17. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored. Thus, we sought to investigate the role of the essential amino acid transporter L-type amino acid transporter 1 (LAT1) in psoriasis. We found that LAT1 expression is increased in KCs and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in KCs 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 imiquimod (IMQ). LAT1 deletion or inhibition by JPH203 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.
Overall, this thesis work underscores the protective role of endogenous Gal-1 in CD8+ T cells in the development of CHS and the novel strategy to control skin inflammation in psoriasis mediated by the IL-23/IL-1β/IL-17 axis through targeting LAT1-mediated amino acid uptake.
