IKZF1 and Ikaros Overexpression Results in Alopecia Areata-Like Phenotype in Mice

Abstract

Ikaros, which is encoded by the Ikaros family zinc finger 1 (IKZF1) gene, is a zinc finger transcription factor. We have previously generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the IKZF1 isoform into epithelial cells expressing keratin 5, which develop patchy alopecia. However, there has been no detailed in vivo investigation of the function of IKZF1 in alopecia or of Ikaros expression in hair follicles of alopecia patients. Our aim was to investigate whether IKZF1 overexpression is involved in the pathogenesis of alopecia areata (AA) using Ikzf1 Tg and to examine Ikaros expression in human scalp skin. We grossly and histologically examined the alopecic lesions of Ikzf1 Tg and the skin of wild-type (WT) mice and the associated mRNA expression of inflammatory mediators. We also examined Ikaros' expression in human scalp skin. Grossly and histologically, we found that the Ikzf1 Tg developed AA-like lesions. Immunohistochemically, the hair follicles of the Ikzf1 Tg expressed high levels of the NKG2D ligand H60 and contained infiltrating CD8⁺NKG2D⁺ T cells. Interleukin 15, tumour necrosis factor-α, CXC chemokine ligand (Cxcl)1, Cxcl10, Cxcl11, signal transducer and activator of transcription (STAT)1, STAT3, Janus kinase (JAK)1 and JAK3 mRNA expression were significantly higher in the alopecic lesions of the Ikzf1 Tg than in the WT mice. Ikzf1 Tg given corticosteroid injections exhibited hair regrowth. Immunohistochemical analysis of scalp hair follicles showed that Ikaros was more highly expressed in AA patients than in non-AA controls. Our study suggests that IKZF1 and Ikaros are involved in the pathogenesis of AA.