J. Immunol. 192, 3383–3389 (2014)

Systemic lupus erythematosus (SLE) is an autoimmune disease where self single-stranded RNA (ssRNA) and double-stranded DNA (dsDNA) are recognized by innate immune system toll-like receptors (TLRs) TLR7 and TLR9 on plasmacytoid dendritic cells (pDCs), leading to inflammation and production of cytokines such as the type I interferon IFN-a. Building on their previous finding linking the endosomal PI(3)P kinase PIKfyve in TLR-dependent production of cytokines IL-12 and IL-23, Cai et al. explored potential roles for PIKfyve in the SLE system. The PIKfyve inhibitor apilimod blocked TLR7- and TLR9-induced expression of type I interferons, including IFN-a in mouse and human pDCs. A mouse model of dysregulated PIKfyve confirmed a role for PIKfyve in TLR-induced IFN-a production. Gene expression analysis showed that apilimod upregulated several genes that had been stimulated by the TLR7 agonist R848, including the transcription factor ATF3, which had already been shown to be a transcriptional repressor for TLR-mediated induction of the cytokine IL-12p40. Chromatin immunoprecipitation experiments support a model where PIKfyve silencing enhances TLR-induced ATF3 expression to promote its binding and silencing of IFN genes. These results uncover a new role for PIKfyve in regulating TLR-induced type I interferons and suggest a potential new approach to SLE treatment.