Fc receptor-like 4 (FcRL4) attenuates B-cell receptor signaling (BCR) while enhancing TLR-responsiveness. FcRL4-mediated BCR dampening is dependent on tyrosine phosphatases SHP1/2. However, regulation of FcRL4 expression and mechanisms underlying FcRL4 amplification of TLR-signaling remain unknown. We find that exposure of human B cells to TLR-2-7 -9 ligands leads to upregulated FcRL4 expression. In FcRL4 transfected B-cell lines, TLR9-induced FcRL4 upregulation was associated with increased HcK expression. Aditionally, p38 inhibition suppressed upregulation of FcRL4 and CD23 but not HcK expression. HcK is an enhancer of TLR-signaling, likely activated by SHP-1/2 and we found that HcK or SHP1/2 inhibition, significantly suppressed TLR9-induced upregulation of CD23. To determine an in vivo relevance for our findings we assessed TLR-stimulated purified FcRL4+ B cells and compared to FcRL4- B cells, FcRL4+ B cells expressed significantly higher levels of the pro-inflammatory cytokine IL-6. Evaluating B cells of HIV+ viremic subjects showed that ex vivo unstimulated FcRL4hi B cell subsets expressed high levels of IL-6. Further, FcRL4+ B cells exhibited high levels of HcK and phosphorylated MAPkinases p38 and Erk .Our data indicate that TLR-activation upregulates FcRL4 expression, and FcRL4 recruited SHP1/2 likely activates HcK thereby amplifying TLR-signaling. Finally, in HIV+ viremic subjects TLR-activated FcRL4+ B cells likely contribute to inflammation via IL-6 expression.
- Copyright © 2013 by The American Association of Immunologists, Inc.