Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice. Moreover, in the human psoriasis SCID mouse model, neutralization of IL-21 reduces both skin thickening and expression of inflammatory molecules, thus supporting the pathogenic role of IL-21 in psoriasis. However, the basic mechanism by which IL-21 promotes skin pathology remains unknown. In this study, we show that CD4(+) cells accumulate early in the dermis of IL-21-treated mice and mediate the development of epidermal hyperplasia. Indeed, IL-21 fails to induce skin damage in RAG1-deficient mice and CD4(+) cell-depleted wild-type mice. The majority of CD4(+) cells infiltrating the dermis of IL-21-treated mice express IFN-γ and, to a lesser extent, IL-17A. Studies in cytokine knockout mice show that IFN-γ, but not IL-17A, is necessary for IL-21-induced epidermal hyperplasia. Finally, we demonstrate that IFN-γ-producing CD4(+) cells infiltrating the human psoriatic plaque express IL-21R, and abrogation of IL-21 signals reduces IFN-γ expression in cultures of psoriatic CD4(+) cells. Data indicate that IL-21 induces an IFN-γ-dependent pathogenic response in vivo, thus contributing to elucidate a mechanism by which IL-21 sustains skin-damaging inflammation.

IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia / M., Sarra; R., Caruso; M. L., Cupi; I., Monteleone; C., Stolfi; E., Campione; L., Diluvio; A., Mazzotta; Botti, Elisabetta; S., Chimenti; Costanzo, Antonio; T. T., Macdonald; F., Pallone; G., Monteleone. - In: JOURNAL OF IMMUNOLOGY. - ISSN 0022-1767. - STAMPA. - 186:(2011), pp. 5435-5442. [10.4049/jimmunol.1003326]

IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia.

BOTTI, ELISABETTA;COSTANZO, ANTONIO;
2011

Abstract

Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice. Moreover, in the human psoriasis SCID mouse model, neutralization of IL-21 reduces both skin thickening and expression of inflammatory molecules, thus supporting the pathogenic role of IL-21 in psoriasis. However, the basic mechanism by which IL-21 promotes skin pathology remains unknown. In this study, we show that CD4(+) cells accumulate early in the dermis of IL-21-treated mice and mediate the development of epidermal hyperplasia. Indeed, IL-21 fails to induce skin damage in RAG1-deficient mice and CD4(+) cell-depleted wild-type mice. The majority of CD4(+) cells infiltrating the dermis of IL-21-treated mice express IFN-γ and, to a lesser extent, IL-17A. Studies in cytokine knockout mice show that IFN-γ, but not IL-17A, is necessary for IL-21-induced epidermal hyperplasia. Finally, we demonstrate that IFN-γ-producing CD4(+) cells infiltrating the human psoriatic plaque express IL-21R, and abrogation of IL-21 signals reduces IFN-γ expression in cultures of psoriatic CD4(+) cells. Data indicate that IL-21 induces an IFN-γ-dependent pathogenic response in vivo, thus contributing to elucidate a mechanism by which IL-21 sustains skin-damaging inflammation.
2011
Animals, CD4-Positive T-Lymphocytes; immunology/metabolism, Cell Separation, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Fluorescent Antibody Technique, Humans, Hyperplasia; pathology, Interferon-gamma; biosynthesis/immunology, Interleukins; immunology/metabolism, Mice, Mice; Inbred C57BL, Mice; Knockout, Psoriasis; immunology/metabolism/pathology, Reverse Transcriptase Polymerase Chain Reaction, Skin; immunology/metabolism/pathology
01 Pubblicazione su rivista::01a Articolo in rivista
IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia / M., Sarra; R., Caruso; M. L., Cupi; I., Monteleone; C., Stolfi; E., Campione; L., Diluvio; A., Mazzotta; Botti, Elisabetta; S., Chimenti; Costanzo, Antonio; T. T., Macdonald; F., Pallone; G., Monteleone. - In: JOURNAL OF IMMUNOLOGY. - ISSN 0022-1767. - STAMPA. - 186:(2011), pp. 5435-5442. [10.4049/jimmunol.1003326]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/625003
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