AP-2a/AP-2b a /AP-2 b Transcription Factors Are Key of Homeostasis

AP-2 transcription factors regulate ectodermal development, but their roles in epidermal homeostasis in adult skin are unknown. We find that AP-2a is the predominant AP-2 family member in adult epidermis, followed by AP-2b. Through inactivation of AP-2a, AP-2b, or both in keratinocytes, we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (i) loss of AP-2b in keratinocytes is compensated for by AP-2a, (ii) loss of AP-2a impairs terminal keratinocyte differentiation and hair morphogenesis, and (iii) the combined loss of AP-2a/AP-2b results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede progressive neutrophilic skin inflammation. Inducible inactivation of AP-2a/AP-2b in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2a or AP-2a/AP-2b in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of reduced AP2a-dependent gene expression of CXCL14 and the keratin 15 gene K15 as an early pathogenic event toward the manifestation of skin inflammation. Thus, AP-2a and AP-2b are critical regulators of epidermal homeostasis in adult skin.