The linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) regulates triggering receptor expressed on myeloid cells (TREM)-2 signaling and macrophage inflammatory responses independently of the linker for activation of T cells.
Triggering receptor expressed on myeloid cells-2 (TREM-2) is rapidly emerging as a key regulator of the innate immune response via its regulation of macrophage inflammatory responses. Here we demonstrate that proximal TREM-2 signaling parallels other DAP12-based receptor systems in its use of Syk and Src-family kinases. However, we find that the linker for activation of T cells (LAT) is severely reduced as monocytes differentiate into macrophages and that TREM-2 exclusively uses the linker for activation of B cells (LAB encoded by the gene Lat2(-/-)) to mediate downstream signaling. LAB is required for TREM-2-mediated activation of Erk1/2 and dampens proximal TREM-2 signals through a novel LAT-independent mechanism resulting in macrophages with proinflammatory properties. Thus, Lat2(-/-) macrophages have increased TREM-2-induced proximal phosphorylation, and lipopolysaccharide stimulation of these cells leads to increased interleukin-10 (IL-10) and decreased IL-12p40 production relative to wild type cells. Together these data identify LAB as a critical, LAT-independent regulator of TREM-2 signaling and macrophage development capable of controlling subsequent inflammatory responses.
Whittaker
Gillian C
GC
Cancer and Inflammation Program, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Orr
Selinda J
SJ
Quigley
Laura
L
Hughes
Laurel
L
Francischetti
Ivo M B
IM
Zhang
Weigou
W
McVicar
Daniel W
DW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D027301:Fusion Regulatory Protein 1, Light Chains / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D027182:Amino Acid Transport System y+; D027301:Fusion Regulatory Protein 1, Light Chains; D051380:GRB2 Adaptor Protein; D053762:Interleukin-12 Subunit p40; C491734:Lat protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011971:Receptors, Immunologic; C518286:SLC7A8 protein, mouse; C498716:Trem2 protein, mouse; D016753:Interleukin-10