Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes 4737

Abstract Description Distinct expression of the alarmins S100A8 (A8), S100A9 (A9) and their antimicrobial Calprotectin (CP) hetero-complex has been documented in Inflammatory Skin Diseases (ISDs). The cell-specific functions of A8 and A9 in local and extra-cutaneous manifestations of ISD were evaluated using genetically engineered mouse models (GEMMs). ISDs such as Atopic Dermatitis are accompanied by Osteopenia, a musculoskeletal complication, while skin infections can lead to osteomyelitis and septic arthritis. A9 or A8 were inactivated in epidermal cells or neutrophils in the JunB?ep genetic mouse model for skin inflammation. Inactivation of epidermal A9 promoted, while A8 inactivation ameliorated experimental ISD. Skin inflammation was also ameliorated when A9 was inactivated in neutrophils or in all cells. However, complete A9 knock-out was associated with worsened systemic effects, such as neutrophilic inflammation and bone loss. Staphylococcus aureus overgrowth, bone destruction and increased A8 protein expression were also observed in the distal phalanges of the digits. Epidermal A8 inactivation ameliorated bone loss, but promoted bone destruction in the digits, likely through A8-positive neutrophilic infiltrates. These data show that site- and cell-type-specific A8 and A9 expression modulates chronic skin and systemic inflammation. These findings pave the way for novel therapies targeting divergent functions of A8 and A9 to restore homeostasis and prevent systemic complications. Funding Sources Marie Sklodowska-Curie postdoctoral grant INTERACT-101111333, European Research Council. APART-MINT postdoctoral fellowship/11998, Austrian Academy of Sciences (ÖAW). European Research Council Advanced grant (ERC AdG 2016-741888-CSI-Fun). Topic Categories Mucosal and Regional Immunology (MUC)