IL-17 gene transfer in vivo induces bone loss and epidermal hyperplasia with implications for psoriatic arthritis (P3377)

Abstract

Abstract The IL-23/IL-17 axis has been linked with pathologic features of psoriatic arthritis, however the direct role of IL-17 on innate immune cells has not been fully elucidated. We have previously demonstrated that IL-17 in vitro contributes to arthritis pathogenesis by inducing osteoclast differentiation and bone resorption. To validate these findings we overexpressed IL-17A in vivo by combining mini-circle DNA technology with hydrodynamic delivery and performed phenotypic analysis of cell populations by FACS, qPCR, histology and in vivo imaging using nanoprobes. We identified that IL-17 induced two distinct IL-17R+ populations, CD11b+Gr1low and CD11b+Gr1high that differentially contribute to bone erosion and epidermal hyperplasia respectively. Our data show that systemic high levels of IL-17 in the serum induce RANK+/c-fms+ osteoclast precursors within the CD11b+Gr1low fraction. To address the functional importance of these precursors we performed RANKL gene transfer to IL-17 overexpressing mice and noticed a significant increase of serum TRAP that correlated with increased bone erosion by microCT. Accordingly, the increase in the CD11b+Gr1high population correlated with an induction of epidermal hyperplasia, Munro’s microabscesses and hyperproliferative keratinocytes in psoriatic lesions. Collectively our data demonstrate mechanistically the role of innate immune precursor cells in the contribution to bone loss and epidermal hyperplasia, hallmarks of PsA.