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- W4285992550 abstract "Alopecia areata (AA) is an autoimmune hair loss disorder with no cure. We report here that C57BL/6J female mice with germline deficiency in autoimmune regulator (Aire-/-) spontaneously developed AA-like lesions (n=61/98; 62%). Aire-/- lesions exhibited AA hallmarks such as miniaturized hair follicles (HFs), decreased hair width (-29%, p<0.0173) and length (-27%, p=0.0002), and increased lymphocytic infiltrate at the hair bulb (+191% in CD8+ T cells, p=0.0546) relative to body site matched Aire+/+ tissue. Anagen HFs are targeted by CD8+ T cells in AA due to overexpression of MHC class I and upregulation of JAK-STAT signaling. Immunohistology confirmed overexpression of MHC class I (+45%, p=0.0385) and STAT1 (+68%, p=0.0032) in Aire-/- lesions. To explore the keratinocyte-autonomous role of Aire in AA and JAK-STAT signaling, we generated CRISPR/Cas9-mediated AIRE-/- keratinocyte clonal cell lines. AIRE-/- keratinocytes displayed increased JAK1 (+21%) and JAK2 (+60%) activation and elevated STAT1 expression (+114%) after IFN-γ treatment (50 ng/mL, 30 min) relative to AIRE+/+ cells by immunoblot. We also observed substantial downregulation of PIAS1 (-43%), a STAT1 inhibitor and AIRE binding partner, and SOCS1 (-63%) and SOCS2 (-20%), JAK inhibitors, in AIRE-/- keratinocytes. Microscopy confirmed increased nuclear STAT1 localization (+24%, p=0.0011) and decreased nuclear PIAS1 (-47%, p <0.0001) in AIRE-/- keratinocytes compared to AIRE+/+ cells after IFN-γ treatment. Overall, our data suggest that AIRE deficiency in keratinocytes leads to an AA-like molecular signature, AIRE functions as a suppressor of JAK-STAT signaling in keratinocytes, and the Aire-/- mouse can be used as a new model to study AA. Given that patients with AIRE mutations display an array of ectodermal dystrophies (including AA), our findings provide a framework towards understanding the role of Aire in skin and HF biology with hopes of uncovering pathogenic mechanisms in AA and AIRE deficiency disorders." @default.
- W4285992550 created "2022-07-21" @default.
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- W4285992550 date "2022-08-01" @default.
- W4285992550 modified "2023-09-28" @default.
- W4285992550 title "708 Aire deficiency induces upregulation of JAK-STAT signaling in keratinocytes and results in alopecia areata-like lesions in mice" @default.
- W4285992550 doi "https://doi.org/10.1016/j.jid.2022.05.720" @default.
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