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 knock-out 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.
From the Veterans Affairs Medical Center, Gainesville, Florida 32610, the Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida 32610.
Zhihong
Z
Yuan
the Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, Illinois 60612.
Mansoor Ali
MA
Syed
the Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, Illinois 60612.
Dipti
D
Panchal
the Department of Immunology, Pusan University, Yangsan 626-870, Korea, and.
Myungsoo
M
Joo
the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
Marco
M
Colonna
the Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida 32610.
Mark
M
Brantly
From the Veterans Affairs Medical Center, Gainesville, Florida 32610, the Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida 32610, rtsadikot@ufl.edu.
Ruxana T
RT
Sadikot
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D051017:Apoptosis Regulatory Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D011065:Poly(ADP-ribose) Polymerases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D053148:Caspase 3
Cell Death; Inflammation; Lipopolysaccharide (LPS); Macrophage; Macrophages; Tumor