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SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction.

ABSTRACT: Alopecia areata is one of the most common autoimmune diseases resulting from T cell-mediated damage of hair follicles. CD8+ T cells infiltrate hair follicles and are responsible for destruction of hair follicles. However the underlying mechanisms for hair loss remain still obscure. In the present study, we identified that suppressor of cytokine signaling-3 (SOCS3), a classical inhibitor of cytokine signaling, significantly inhibits CD8+T cell maturation, interferon-? (IFN-?) production and alopecia areata. SOCS3 is downregulated in the skin of alopecia areata patients and murine autoimmune alopecia model. Furthermore, SOCS3 treatment prevents the development of alopecia areata in the graft model. SOCS3 decreases the CD44high CD62Llow effector memory CD8+ T cells, resulting in the decrease of IFN-? production. The expression of Fas and major histocompatibility complex-1 (MHC I) is upregulated in skin from C3H/HeJ alopecia areata mice, and this increase is suppressed by SOCS3. The SOCS3 level is negative correlation with the Fas and MHC I level in patients with alopecia areata. These results suggest that SOCS3 treatment may be an effective strategy to treat autoimmune alopecia as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.

SUBMITTER: Gao Z

PROVIDER: S-EPMC5464880 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction.

Gao Zhen Z Jin Yu-Qing YQ Wu Wei W

Oncotarget 20170501 20

Alopecia areata is one of the most common autoimmune diseases resulting from T cell-mediated damage of hair follicles. CD8+ T cells infiltrate hair follicles and are responsible for destruction of hair follicles. However the underlying mechanisms for hair loss remain still obscure. In the present study, we identified that suppressor of cytokine signaling-3 (SOCS3), a classical inhibitor of cytokine signaling, significantly inhibits CD8+T cell maturation, interferon-γ (IFN-γ) production and alope ...[more]

PMID: 28418931

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Project description:One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56+/NKG2D+ cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies. AA is thought to arise when the hair follicle's (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8+ T cells. In common with other autoimmune diseases, upregulation of IFN-γ and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3. The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-γ and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8+ T cells and NKG2D+ cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases.

Project description:The treatment of autoimmune diseases still poses a major challenge, frequently relying on non-specific immunosuppressive drugs. Current efforts aim at reestablishing self tolerance using immune cells with suppressive activity like the regulatory T cells (Treg) or the myeloid-derived suppressor cells (MDSC). We have demonstrated therapeutic efficacy of MDSC in mouse Alopecia Areata (AA). In the same AA model, we now asked whether MDSC exosomes (MDSC-Exo) can replace MDSC. MDSC-Exo from bone marrow cells (BMC) cultures of healthy donors could substantially facilitate treatment. With knowledge on MDSC-Exo being limited, their suitability needs to be verified in advance. Protein marker profiles suggest comparability of BMC- to ex vivo collected inflammatory MDSC/MDSC-Exo in mice with a chronic contact dermatitis, which is a therapeutic option in AA. Proteome analyses substantiated a large overlap of function-relevant molecules in MDSC and MDSC-Exo. Furthermore, MDSC-Exo are taken up by T cells, macrophages, NK, and most avidly by Treg and MDSC-Exo uptake exceeds binding of MDSC themselves. In AA mice, MDSC-Exo preferentially target skin-draining lymph nodes and cells in the vicinity of remnant hair follicles. MDSC-Exo uptake is accompanied by a strong increase in Treg, reduced T helper proliferation, mitigated cytotoxic activity, and a slight increase in lymphocyte apoptosis. Repeated MDSC-Exo application in florid AA prevented progression and sufficed for partial hair regrowth. Deep sequencing of lymphocyte mRNA from these mice revealed a significant increase in immunoregulatory mRNA, including FoxP3 and arginase 1. Downregulated mRNA was preferentially engaged in prohibiting T cell hyperreactivity. Taken together, proteome analysis provided important insights into potential MDSC-Exo activities, these Exo preferentially homing into AA-affected organs. Most importantly, changes in leukocyte mRNA seen after treatment of AA mice with MDSC-Exo sustainably supports the strong impact on the adaptive and the non-adaptive immune system, with Treg expansion being a dominant feature. Thus, MDSC-Exo could potentially serve as therapeutic agents in treating AA and other autoimmune diseases.

Dataset Information

SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction.

Publications

SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction.

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