Persistent activation of STAT6 in keratinocytes elicits neutrophilic skin inflammation, pruritus and <i>S. aureus</i> colonization reminiscent of chronic atopic dermatitis

Abstract Atopic dermatitis (AD) evolves from initial type 2 immunity-driven inflammation to chronic mixed responses by poorly understood mechanisms. To investigate how the prolonged activation of the usually IL-4/IL-13-induced transcription factor STAT6 in keratinocytes impacts on the development and subtype of AD, we generated a new mouse model in which a constitutively active form of STAT6 is selectively expressed in keratinocytes. These K14Cre + STAT6 vt/vt mice spontaneously developed AD-like skin lesions characterized by Staphylococcus aureus colonization, neutrophilic inflammation, and pruritus starting at the age of 12-14 weeks. Treatment with antibiotics mitigated pathology, indicating that it is microbiota-driven. Comparison of human AD gene expression data with the transcriptome of skin biopsies from K14Cre + STAT6 vt/vt mice revealed features shared with chronic AD, including genes associated with neutrophil and keratinocyte activation. Furthermore, heterozygous K14Cre + STAT6 vt/wt mice developed a mixed eosinophilic and neutrophilic skin inflammation with exacerbated pathology compared to wild-type controls in an induced model of atopic dermatitis, compatible with chronic AD. These results indicate that persistent STAT6 activity in keratinocytes facilitates S. aureus outgrowth on the skin, promotes a type 1-/type 3-biased immune response, and is sufficient to mimic the transition from acute type 2 immunity-to chronic type 1-/type 3-immunity-dominated AD.