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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.

Publication ,  Journal Article
Whittaker, GC; Orr, SJ; Quigley, L; Hughes, L; Francischetti, IMB; Zhang, W; McVicar, DW
Published in: J Biol Chem
January 29, 2010

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.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

January 29, 2010

Volume

285

Issue

5

Start / End Page

2976 / 2985

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Signal Transduction
  • Receptors, Immunologic
  • Phosphoproteins
  • Mice, Inbred C57BL
  • Mice
  • Membrane Proteins
  • Membrane Glycoproteins
  • Macrophages
  • Lymphocyte Activation
 

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Whittaker, G. C., Orr, S. J., Quigley, L., Hughes, L., Francischetti, I. M. B., Zhang, W., & McVicar, D. 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. J Biol Chem, 285(5), 2976–2985. https://doi.org/10.1074/jbc.M109.038398
Whittaker, Gillian C., Selinda J. Orr, Laura Quigley, Laurel Hughes, Ivo M. B. Francischetti, Weigou Zhang, and Daniel W. McVicar. “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.J Biol Chem 285, no. 5 (January 29, 2010): 2976–85. https://doi.org/10.1074/jbc.M109.038398.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

January 29, 2010

Volume

285

Issue

5

Start / End Page

2976 / 2985

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Signal Transduction
  • Receptors, Immunologic
  • Phosphoproteins
  • Mice, Inbred C57BL
  • Mice
  • Membrane Proteins
  • Membrane Glycoproteins
  • Macrophages
  • Lymphocyte Activation