Genetic deletion of S100A9 fails to abrogate psoriasiform inflammation in the KC-Tie2 mouse model due to IL-12/23 compensation. (CAM5P.237)

Abstract

Abstract The proinflammatory proteins S100A8/9 are purported to play a pathogenic role in psoriasis. A recent report showed genetic deletion of S100A9 strongly attenuated ear skin inflammation in the K5-JunB:Jun mouse and imiquimod skin inflammation models. We previously reported increased expression of S100A8/9 (>135-fold; P<0.05) in the KC-Tie2 psoriasis mouse model, with expression downregulated following disease reversal. We sought to confirm the importance of S100A9 in disease pathogenesis and mated KC-Tie2 mice with S100A9 KO mice. In contrast to recent reports, KC-Tie2-S100A9 KO mice (n=11) had similar levels of skin inflammation (acanthosis), T cell and myeloid cell skin-infiltration as KC-Tie2 mice (n=9); despite significantly decreased levels of DefB4, IL-1α, IL-17C and TNFα (all P<0.05). Interestingly, KC-Tie2-S100A9 KO animals had significantly elevated splenic and skin-draining CD11b+Ly-6C+ pro-inflammatory monocytes (27% and 86%, respectively; P<0.05) compared to KC-Tie2 animals, increased expression of skin IL-12/23 and IL-17A/F and sustained levels of skin IFNγ, IL-22, IL-6 and KLK6, potentially explaining the sustained presence of disease. These results suggest that the IL-23-Th17 inflammatory axis may compensate for genetic ablation of S100A9 and sustain psoriasiform skin inflammation in KC-Tie2 animals. Thus, the role of S100A9 in skin inflammation may be model dependent and further investigation is needed to establish S100A9 as a therapeutic target in psoriasis.