Inflammatory skin diseases (ISD) such as atopic dermatitis (AD) are common conditions affecting 5-10% people worldwide. Microbiota dysbiosis and deregulation of antimicrobial peptides (AMPs), including S100A8 (A8), S100A9 (A9) and their heterodimer Calprotectin (CP) have been documented in ISD. However, their function in skin inflammation is still not understood. Therefore, to decipher the role of A8, A9 and CP in skin inflammation genetically engineered mouse models (GEMMs) were used. Mice with constitutive Keratin 5-dependent epidermal deletion of JunB (JunB∆ep) present skin inflammation with macroscopic lesions and Staphylococcus aureus colonization reminiscent of AD. This GEMM displays mTOR signaling hyperactivation in lesional skin as well as systemic inflammation with multi-organ involvement. In the lesional skin of JunB∆ep mice increased expression of A8 and A9 was observed as well as significant increase of A8, A9 and CP in serum and stool. Global inactivation of A9 in JunB∆ep mice decreased A8 expression and substantially improved skin macroscopic lesions. Inflammatory mediators including G-CSF, IL-17, IL-6 and IL-33 as well as S. aureus colonization were also decreased in skin. Importantly, the absence of A9 in JunB∆ep mice diminished mTOR signaling in the skin and reduced levels of inflammasome pathway-mediators including Nlrp3, Aim2, Caspase-1 and Il-1β. However, global inactivation of A9 in JunB∆ep mice exacerbated systemic inflammation and induced prominent swelling of digits. These results reveal a complex involvement of A8, A9 and CP in the development of local and systemic inflammation originating in the skin, supporting a role of AMPs in ISD. Ongoing experiments aim to identify the specific A8- and A9-expressing cells involved in ISD and to determine the critical targets connected to A8, A9 and/or CP to prevent or ameliorate ISD.

ESDRLB004 - The role of S100A8, S100A9 and Calprotectin in skin inflammation

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING