RESUMEN
IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRß(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRß(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRß(+) T cells and ILCs.
Asunto(s)
Aminoquinolinas/efectos adversos , Quimiotaxis/inmunología , Interleucinas/biosíntesis , Psoriasis/etiología , Psoriasis/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Proliferación Celular , Quimiotaxis/genética , Modelos Animales de Enfermedad , Imiquimod , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Interleucinas/genética , Ratones , Ratones Noqueados , Psoriasis/patología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Interleucina-22RESUMEN
Psoriasis is a common chronic autoimmune skin disease of unknown cause that involves dysregulated interplay between immune cells and keratinocytes. IL-22 is a cytokine produced by the TH1, TH17, and TH22 subsets that are functionally implicated in the psoriatic pathology. We assessed the role of IL-22 in a mouse model where psoriasiform skin inflammation is triggered by topical application of the TLR7/8 agonist imiquimod. At the macroscopic level, scaly skin lesions induced by daily applications of imiquimod in wild-type mice were almost totally absent in IL-22-deficient mice or in mice treated with a blocking anti-IL-22 Ab. At the microscopic level, IL-22-deficient mice showed a dramatic decrease in the development of pustules and a partial decrease in acanthosis. At the molecular level, the absence or inhibition of IL-22 strongly decreased the expression of chemotactic factors such as CCL3 and CXCL3 and of biomarkers such as S100A8, S100A7, and keratin 14, which reflect the antimicrobial and hyperproliferative responses of keratinocytes. IL-22 also played a major role in neutrophil infiltration after imiquimod treatment. IL-23 was required for IL-22 production, and γδ TCR lymphocytes represented the major source of IL-22 in lymph nodes from imiquimod-treated mice. However, T cells were not absolutely required for IL-22 production because imiquimod-induced IL-22 expression in the skin is still preserved in Rag2(-/-) mice. Taken together, our data show that IL-22 is required for psoriasis-like lesions in the mouse imiquimod model and is produced by both T cells and innate immune cells.
Asunto(s)
Adyuvantes Inmunológicos/efectos adversos , Aminoquinolinas/efectos adversos , Dermatitis/inmunología , Interleucinas/inmunología , Psoriasis/inmunología , Piel/inmunología , Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Quimiocina CCL3/genética , Quimiocina CCL3/inmunología , Quimiocina CCL3/metabolismo , Dermatitis/etiología , Dermatitis/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Imiquimod , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Interleucinas/biosíntesis , Interleucinas/genética , Ratones , Ratones Noqueados , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/genética , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Psoriasis/inducido químicamente , Psoriasis/metabolismo , Psoriasis/patología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Piel/metabolismo , Piel/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Interleucina-22RESUMEN
Para-Phenylenediamine (PPD) is an aromatic amine used in hair dyes and in temporary black henna tattoos, which is a frequent cause of allergic contact dermatitis (ACD). ACD is a skin inflammatory reaction characterized by modifications such as spongiosis, exocytosis and acanthosis. The aim of this study is to characterize the expression and the role of IL-20-related cytokines, including IL-19, IL-20, IL-22 and IL-24, in ACD. The expression of IL19, IL20, IL22 and IL24 is increased in affected skin from PPD allergic patients compared with uninvolved skin. In addition, the expression of these cytokines positively correlates with clinical symptoms. To assess their role in ACD, we set up a mouse model of PPD-induced allergic contact dermatitis and we showed that, in contrast to Il22-deficient mice, Il22ra1-, Il20rb- and Il24-deficient mice are partially protected against development of PPD-induced contact hypersensitivity. These mice have decreased ear thickening and less acanthosis compared with WT mice after PPD treatment. In addition, the absence of IL-22R, IL-20R2 or IL-24 affects the recruitment of neutrophils into the skin but not the total IgE production. Taken together, these results demonstrate the implication of IL-24 via the IL-20R type II receptor in the inflammatory process of ACD.