Cutting Edge: BCAP Promotes Lupus-like Disease and TLR-Mediated Type I IFN Induction in Plasmacytoid Dendritic Cells.

ABSTRACT: Systemic lupus erythematosus severity correlates with elevated serum levels of type I IFNs, cytokines produced in large quantities by plasmacytoid dendritic cells (pDC) in response to engagement of TLR7 and TLR9 with endocytosed nucleic acids. B cell adaptor for PI3K (BCAP) promoted many aspects of TLR7-driven lupus-like disease, including Isg15 and Ifit1 expression in blood and an immature pDC phenotype associated with higher IFN production. BCAP-/- mice produced significantly less serum IFN-? than wild-type mice after injection of TLR9 agonist, and BCAP promoted TLR7 and TLR9-induced IFN-? production specifically in pDC. TLR-induced IFN-? production in pDC requires DOCK2-mediated activation of Rac1 leading to activation of IKK?, a mechanism we show was dependent on BCAP. BCAP-/- pDC had decreased actin polymerization and Rac1 activation and reduced IKK? phosphorylation upon TLR9 stimulation. We show a novel role for BCAP in promoting TLR-induced IFN-? production in pDC and in systemic lupus erythematosus pathogenesis.

SUBMITTER: Chu T 

PROVIDER: S-EPMC6516743 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature