Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes

Abstract

Increased expression of the homodimeric S100A8 (A8) and S100A9 (A9) alarmins and their Calprotectin (CP) antimicrobial hetero-complex has been reported in Inflammatory Skin Diseases (ISDs) such as Atopic Dermatitis (AD), but the functional consequences of this increase are not known. We evaluated the cell- and tissue-specific functions of A8 and A9 in the local and the extra-cutaneous manifestations of ISD using genetically engineered mouse models. The genes encoding for the A9 or A8 proteins were inactivated in epidermal cells or neutrophils in the JunB^∆ep genetic mouse model for AD. Overall, epidermal inactivation of A9 aggravated, while similar A8 inactivation ameliorated experimental ISD. Epidermal differentiation and 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. In addition, the distal phalanges of the digits displayed increased A8 protein expression, SA overgrowth and bone destruction. 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 with distinct effects on the skin differentiation and on the musculoskeletal system. These findings pave the way for novel therapies targeting the divergent functions of A8 and A9 to restore epidermal homeostasis and prevent systemic complications.