BCAP promotes Lupus-like disease and regulates IFNα production in pDC

Abstract

Abstract Systemic lupus erythematosus (SLE) severity is correlated with elevated serum type I interferons (IFN), mainly IFNα, which is produced in large amounts by pDC in response to nucleic acid sensing by TLR7 and TLR9. TLR7 and TLR9-induced IRF7 translocation to the nucleus and subsequent IFNα production by pDC is dependent on phosphatidylinositol-3 kinase (PI3K), but how PI3K regulates this process remains undefined. We showed that B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation in macrophages, thus we asked if BCAP plays a role in pDC IFNα production and SLE pathogenesis. We show BCAP promoted many aspects of TLR7-driven lupus-like disease including interferon-stimulated gene expression in blood. BCAP promoted TLR7 and TLR9-induced IFNα production in pDC, and BCAP−/− mice produced significantly less serum IFNα after injection of TLR9 agonist than WT mice, consistent with a pDC IFNα defect. TLR-induced IFNα production in pDC involves dual signaling pathways that run in parallel and converge upon the phosphorylation and activation of IKKα. There is a TLR-independent pathway initiated by nucleic acid recognition at the plasma membrane that involves Dock2-mediated activation of Rac1, required for phosphorylation of IKKα. The TLR-dependent pathway occurs upon nucleic acid recognition by endosomal TLR7 or 9 and leads to MyD88 activation. BCAP regulated IFNα production independently of the TLR-MyD88 pathway and both BCAP and PI3K were required for CpG DNA-induced early actin remodeling, a readout of Rac1 activation, and IKKα phosphorylation in pDC. Our data suggest BCAP and PI3K specifically regulate the TLR-parallel pathway in pDC. Overall, we show a novel role for BCAP in regulating IFNα production in pDC and SLE pathogenesis.