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* German Cancer Research Center (DKFZ), Division of Innate Immunity, Heidelberg, Germany, Europe; and
Academy of Sciences of the Czech Republic, Institute of Molecular Genetics, Prague, Czech Republic, Europe
The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-
and IL-8 production and enhances inflammatory responses to microbial products. For signal transduction, TREM-1 couples to the ITAM-containing adapter DNAX activation protein of 12 kDa (DAP12). In general, ITAM-mediated signals lead to cell activation, although DAP12 was recently implicated in inhibitory signaling in mouse macrophages and dendritic cells. To date, signals downstream of the TREM-1 and DAP12 complex in myeloid cells are poorly defined. By analyzing receptor-induced tyrosine phosphorylation patterns, we discovered that the ligation of TREM-1 leads to tyrosine phosphorylation of the non-T cell activation linker (NTAL; also called linker of activation in B cells or LAB) in a myelomonocytic cell line and primary human granulocytes. Using RNA interference to decrease the expression levels of NTAL, we demonstrate that in NTAL knockdown cell lines the phosphorylation of ERK1/2 is enhanced. In addition, low levels of NTAL are correlated with decreased and delayed mobilization of Ca2+ after TREM-1 triggering. Most importantly, we demonstrate that NTAL acts as a negative regulator of TNF- and IL-8 production after stimulation via TREM-1. Our results show that activation signals delivered via DAP12 can be counterbalanced by the adaptor NTAL, identifying NTAL as gatekeeper of TREM-1/DAP12-induced signaling in myeloid cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Marie Curie Excellence Grant 002739 (to A.C.).
2 Address correspondence and reprint requests to Dr. Adelheid Cerwenka, German Cancer Research Center (DKFZ/D080), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail address: a.cerwenka{at}dkfz.de
3 Abbreviations used in this paper: DAP12, DNAX activation protein of 12 kDa; DN, dominant negative; Grb2, growth factor receptor-bound protein 2; LAT, linker of activation in T cells; LM, laurylmaltoside; LNGFR, low affinity nerve growth factor receptor; NTAL, non-T cell activation linker; N4, NTAL-4; N5, NTAL-5; PLC-
, phospholipase C-; pY, phosphotyrosine; SBP, streptavidin binding peptide; shRNA, short hairpin RNA; siRNA, small interfering RNA; S6H, streptavidin binding peptide-6xHis; TREM-1, triggering receptor expressed on myeloid cells; U937-TD, U937 cells expressing TREM-1/DAP12; VC, empty vector control.
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