LAB/NTAL Regulates DAP12 Signaling and Macrophage Differentiation (B163)

Recent studies have highlighted a significant, yet controversial role for DAP12 in the suppression of Toll receptor (TLR)-mediated inflammatory cytokine production by macrophages and plasmacytoid DC. Here we report that the Linker for Activation of T cells (LAT) and the Linker for Activation of B Cells (LAB) are critically regulated during myeloid development such that macrophages express LAB but little if any LAT. Consistent with LAB as a primary adaptor in macrophages, we readily observed its DAP12-inducible phosphorylation. Analogous to its role in Mast cells, we found that LAB also attenuates DAP12 signaling, however, the increased signaling in LAB−/− MΦ was not the result of increased utilization of LAT. Instead, LAB nucleated a DAP12-induced complex containing the E3 ligase c-Cbl and the p85 regulatory domain of PI3K. In the absence of LAB, DAP12-induced MAPK activation was ablated whereas c-Cbl was hyperphosphorylated resulting in enhanced p85/c-Cbl interactions. MΦ of DAP12 or TREM2−/− mice exhibit global increases in TLR-induced cytokine production, yet LPS stimulated LAB−/− BMM_ demonstrated increased IL-10 and decreased IL-12 p40 production. Together these data suggest that the utilization of LAB by TREM-2/DAP12 facilitates Erk1/2 activation while suppressing proximal signaling so as to yield macrophages with the appropriate balance of pro- and anti-inflammatory responses.