139 Cell-specific immune-modulatory functions of S100A8/A9 in Atopic Dermatitis

Inflammatory skin diseases (ISDs) comprise a series of complex pathologies, such as Atopic Dermatitis (AD), which accounts for the largest ISD burden. Despite major efforts to gain insight into the cellular and molecular mechanisms underlying AD effective treatment is lacking. AD is accompanied by microbial dysbiosis, characterized by Staphylococcus aureus (SA) colonization, and deregulation of alarmin expression. Among the alarmins are the S100A8 (A8), S100A9 (A9) proteins that form homo and heterodimers as well as the A8/A9 hetero-tetrameric complex termed Calprotectin, mainly expressed by keratinocytes and neutrophils. The cell-specific contribution of A8 and A9 to SA and systemic inflammation is still elusive. We employed a genetically engineered mouse model of AD with constitutive epidermal loss of JunB (JunBΔep). JunBΔep mice were crossed with either global A9 knock-outs (JunBΔepS100a9-/-) or epidermal-deficient A9 mice (JunBΔepS100a9Δep). Global A9 inactivation in JunBΔep mice ameliorated AD-like skin lesions, reduced SA colonization and neutrophil recruitment, and decreased inflammatory mediators in the skin, including A8, IL-17, IL-6, Myeloperoxidase and Neutrophil elastase. In addition, JunBΔepS100a9-/- mice developed aggravated systemic inflammation with swollen digits, SA overgrowth, bone erosion and local A8 upregulation. On the other hand, when A9 was inactivated only in epidermal cells, JunBΔepS100a9Δep mice displayed worsened skin lesions, increased SA colonization and increased A8/A9-positive neutrophil recruitment, as well as elevated blood granulocytes and A8 homodimers. JunBΔep mice with A9-deficient myeloid cells were next established by bone marrow transplantation of JunBΔep mice with bone marrow from mice with Mrp8-Cre-mediated A9 deletion. A9-deficiency in neutrophils improved skin lesions in JunBΔep mice and reduced A8 levels in the skin, but had no effect on systemic inflammation. Our results suggest that in a given cellular context A8 homodimers contributes to skin and systemic inflammation and reveal a protective function of epithelial A9 in AD-like disease, whereas neutrophil-derived A9 complexes are pro-inflammatory.