Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12

DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. RANKL (Receptor Activator for NFkB ligand or TNFSF25), a TNF (tumor necrosis factor) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by ITAM (immunoreceptor tyrosine-based activation motif)-signaling adaptors, DAP12 (DNAX associated protein 12kD size) and FcRγ (FcεR1 gamma chain). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain, and therefore must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including TREM-2 (Triggering Receptor Expressed on Myeloid Cells 2), MDL-1 (Myeloid Dap-12 associated Lectin) and Siglec-15 (Sialic acid-binding immunoglobulin-type lectin15), while FcRγ pairs with a different set of receptors including OSCAR (Osteoclast Specific Activating Receptor), PIR-A (Paired Immunoglobulin Receptor A), and Fc Receptors. The ligands for many of these receptor in the bone microenvironment remain unknown. Here we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis, However, co-stimulation and the effects of ITAM-signaling have turned out to be complex including paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and ITIM (immunoreceptor tyrosine-based inhibitory motif) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis