Btk is a positive regulator in the TREM-1/DAP12 signaling pathway.

The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering.

The TREM-1/DAP12 pathway.

DNAX activation protein of 12kDa (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter, which couples to multiple receptors expressed on natural killer (NK) cells, monocytes, and neutrophils. Initially, DAP12-mediated signaling was mainly investigated downstream of receptors expressed on NK cells. In myeloid cells, one of the receptors associating with DAP12 is the triggering receptor expressed on myeloid cells (TREM)-1.

Non-T cell activation linker (NTAL) negatively regulates TREM-1/DAP12-induced inflammatory cytokine production in myeloid cells.

The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-alpha and IL-8 production and enhances inflammatory responses to microbial products. For signal transduction, TREM-1 couples to the ITAM-containing adapter DNAX activation protein of 12 kDa (DAP12). In general, ITAM-mediated signals lead to cell activation, although DAP12 was recently implicated in inhibitory signaling in mouse macrophages and dendritic cells.