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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

Whittaker, Gillian C., Orr, Selinda Jane, Quigley, Laura, Hughes, Laurel, Francischetti, Ivo M. B., Zhang, Weigou and McVicar, Daniel W. 2010. 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. Journal of Biological Chemistry 285 (5) , pp. 2976-2985. 10.1074/jbc.M109.038398

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
Uncontrolled Keywords: Immunology; Immunology/Innate Immunity; Receptors/Leukocyte/Lymphocyte; Signal Transduction/Adapter Proteins; Signal Transduction/Phosphotyrosine; Signal Transduction/Phosphotyrosine/SH2 Domains; Macrophage
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Last Modified: 04 Jun 2017 05:06
URI: http://orca-mwe.cf.ac.uk/id/eprint/48541

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