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.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Whittaker, GC; Orr, SJ; Quigley, L; Hughes, L; Francischetti, IMB; Zhang, W; McVicar, DW

Published Date

  • January 29, 2010

Published In

Volume / Issue

  • 285 / 5

Start / End Page

  • 2976 - 2985

PubMed ID

  • 19948717

Pubmed Central ID

  • 19948717

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.038398

Language

  • eng

Conference Location

  • United States