IntroductionTREM-1 belongs to the immunoglobulin (Ig)-like superfamily of receptors. In humans, TREM-1 is expressed on neutrophils and CD14 high monocytes. 1 TREM-1 expression is further up-regulated by TLR ligands. Binding of TREM-1 to endogenous ligand(s) expressed on granulocytes and platelets and present in sera of septic patients, 2-4 as well as to exogenous ligands on Marburg and Ebola viruses, 5 has been described. The exact nature of TREM-1 ligand(s), however, remains elusive. Engagement of TREM-1 by agonistic monoclonal antibodies (mAbs) results in respiratory burst, degranulation, phagocytosis, secretion of pro-inflammatory cytokines such as TNF-␣, of the chemokines, IL-8 and monocyte chemotactic protein-1 (MCP-1), and in the up-regulation of cell surface expressed differentiation/activation markers. 1 In animal models of lipopolysacharide (LPS)-induced septic shock and microbial sepsis caused by live Escherichia coli, application of a soluble TREM-1-Ig fusion protein greatly increased survival of experimental animals indicating the importance of TREM-1 in the amplification of inflammation. 6 TREM-1 possesses a short intracellular part that lacks intrinsic signaling motifs. Instead, it is coupled to the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor protein, DAP12. 1 TREM-1 engagement leads to Ca 2ϩ mobilization and phosphorylation of several proteins including DAP12, extracellular-signal regulated kinase (Erk1/2), phospholipase C␥ (PLC␥) 1 and the adaptor protein NTAL that further interacts with Grb2. 7 Recently, it was reported that the adaptor protein CARD9 is essential for TREM-1-induced secretion of TNF-␣, IL-2 and IL-12p40 by mouse bone marrow-derived dendritic cells (BMDCs). 8 Bruton tyrosine kinase (Btk), a member of the Tec family of protein tyrosine kinases (PTKs), is involved in signaling via a variety of receptors including the B-cell receptor (BCR), cytokine receptors and integrins. 9,10 Loss of Btk function causes X-linked agammaglobulinemia (XLA), a rare primary immunodeficiency disease. 11,12 Mutations causing XLA have been described in all Btk domains as well as in noncoding sequences of the gene. 13 XLA is manifested by severe defects in early B-cell development, resulting in an almost complete absence of peripheral B cells and Igs of all classes. Affected individuals suffer from recurrent bacterial and enteroviral infections. 9 In mice, the R28C point mutation in the pleckstrin homology (PH) domain of Btk leads to X-linked immunodeficiency (Xid). 14 In innate immune cells, the role of Btk is less clear. Btk has been implicated in several pathways in myeloid cells. 10 Btk associates with certain TLRs and their downstream signaling molecules. 15 Contradictory results were obtained from studies of TLR stimulation of monocytes of XLA patients. In one report, relative to healthy controls, monocytes of XLA patients secreted reduced amounts of TNF-␣ upon LPS stimulation. 16 On the other hand, Perez et al 17 described that monocytes of XLA patients showed similar TN...