Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells that plays an important role in the amplification of inflammation. Recent studies suggest a role for TREM-1 in tumor-associated macrophages with relationship to tumor growth and progression. Whether the effects of TREM-1 on inflammation and tumor growth are mediated by an alteration in cell survival signaling is not known. In these studies, we show that TREM-1 knock-out macrophages exhibit an increase in apoptosis of cells in response to lipopolysaccharide (LPS) suggesting a role for TREM-1 in macrophage survival. Specific ligation of TREM-1 with monoclonal TREM-1 (mTREM-1) or overexpression of TREM-1 with adeno-TREM-1 induced B-cell lymphoma-2 (Bcl-2) with depletion of the key executioner caspase-3 prevents the cleavage of poly(ADP-ribose) polymerase. TREM-1 knockout cells showed lack of induction of Bcl2 with an increase in caspase-3 activation in response to lipopolysaccharide. In addition overexpression of TREM-1 with adeno-TREM-1 led to an increase in mitofusins (MFN1 and MFN2) and knockdown of TREM-1 decreased the expression of mitofusins suggesting that TREM-1 contributes to the maintenance of mitochondrial integrity favoring cell survival. Investigations into potential mechanisms by which TREM-1 alters cell survival showed that TREM-1-induced Bcl-2 in an Egr2-dependent manner. Furthermore, our data shows that expression of Egr2 in response to specific ligation of TREM-1 is ERK mediated. These data for the first time provide novel mechanistic insights into the role of TREM-1 as an anti-apoptotic protein that prolongs macrophage survival.