Bruton's Tyrosine Kinase and Protein Kinase C μ Are Required for TLR7/9-Induced IKKα and IRF-1 Activation and Interferon-β Production in Conventional Dendritic Cells

Stimulation of TLR7/9 by their respective ligands leads to the activation of I kappa B kinase alpha (IKK alpha) and Interferon Regulatory Factor 1 (IRF-1) and results in interferon (IFN)-beta production in conventional dendritic cells (cDC). However, which other signaling molecules are involved in IKKa and IRF-1 activation during TLR7/9 signaling pathway are not known. We and others have shown that Bruton's Tyrosine Kinase (BTK) played a part in TLR9-mediated cytokine production in B cells and macrophages. However, it is unclear if BTK participates in TLR7/9-induced IFN-beta production in cDC. In this study, we show that BTK is required for IFN-beta synthesis in cDC upon TLR7/9 stimulation and that stimulated BTK-deficient cDC are defective in the induction of IKK alpha/beta phosphorylation and IRF-1 activation. In addition, we demonstrate that Protein Kinase C m (PKC mu) is also required for TLR7/9-induced IRF-1 activation and IFN-beta upregulation in cDC and acts downstream of BTK. Taken together, we have uncovered two new molecules, BTK and PKCm, that are involved in TLR7/9-triggered IFN-beta production in cDC.