Identification of polo-like kinase as a therapeutic target in murine lupus

Introduction. The signalling cascades that contribute to lupus pathogenesis are incompletely understood. We address this by using an unbiased activity-based kinome screen of murine lupus. Methods. An unbiased activity-based kinome screen (ABKS) of 196 kinases was applied to two genetically different murine lupus strains. Systemic and renal lupus were evaluated following in vivo PLK1blockade. The upstream regulators and downstream targets of PLK1 were also interrogated. Results. Multiple signalling cascades were noted to be more active in murine lupus spleens, including PLK1. In vivo administration of a PLK1-specific inhibitor ameliorated splenomegaly, anti-dsDNA antibody production, proteinuria, BUN and renal pathology in MRL./pr mice (P < 0.05). Serum IL-6, IL-17 and kidney injury molecule 1 (KIM-1) were significantly decreased after PLK1 inhibition. PLK1 inhibition reduced germinal centre and marginal zone B cells in the spleen, but changes in T cells were not significant. In vitro, splenocytes were treated with anti-mouse CD40 Ab or F(ab')2 fragment anti-mouse IgM. After 24-h stimulation, IL-6 secretion was significantly reduced upon PLK1 blockade, whereas IL-10 production was significantly increased. The phosphorylation of mTOR was assessed in splenocyte subsets, which revealed a significant change in myeloid cells. PLK1 blockade reduced phosphorylation associated with mTOR signalling, while Aurora-A emerged as a potential upstream regulator of PLK1. Conclusion. The Aurora-A -> PLK1 -> mTOR signalling axis may be central in lupus pathogenesis, and emerges as a potential therapeutic target.