BCAP negatively regulates TLR signaling in macrophages (116.13)

Abstract

Abstract B cell adaptor for phosphoinositide 3-kinase (BCAP) was originally identified as an adaptor molecule that binds to the p85 subunit of phosphatidylinositol 3-kinase (PI3K). BCAP-deficient mice have decreased numbers of mature B cells and attenuated B cell function due to defects in B cell receptor signaling. BCAP is also expressed in macrophages and activates PI3K downstream of Toll-like receptor (TLR) ligation. Here we investigated the responses of BCAP-deficient mice to stimulation through TLRs. BCAP-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli in vitro. Additionally, BCAP-deficient mice produced more IL-12 in response to LPS in vivo. The TLR mediated Akt activation is impaired in BCAP-deficient macrophages. Furthermore, the PI3K inhibitor wortmannin enhanced TLR mediated proinflammatory cytokine production in wild type but not in BCAP-deficient macrophages. In B cells, YXXM motifs of BCAP are required for BCR induced PI3K activation. Surprisingly, we found that YXXM motifs of BCAP are only partially responsible for the BCAP mediated negative regulation of TLR signaling in macrophages. BCAP is constitutively phosphorylated and associated with PI3K in resting macrophages, and, unlike in B cells, does not require Syk for its phosphorylation. Taken together, our findings show that BCAP negatively regulates TLR signaling in macrophages partly through regulation of TLR-mediated PI3K activation.