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000143556 0247_ $$2doi$$a10.1038/s41423-018-0003-5
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000143556 037__ $$aDKFZ-2019-01137
000143556 041__ $$aeng
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000143556 1001_ $$aCarrasco, Kevin$$b0
000143556 245__ $$aTREM-1 multimerization is essential for its activation on monocytes and neutrophils.
000143556 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2019
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000143556 520__ $$aThe triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor expressed on innate immune cells. By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors (TLRs), TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases, such as septic shock, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. However, the molecular events leading to the activation of TREM-1 in innate immune cells remain unknown. Here, we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca2+ release, reactive oxygen species, and cytokine production correlate with the degree of TREM-1 aggregation. TREM-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface, in contrast to primary human neutrophils, where LPS induced a rapid cell membrane reorganization of TREM-1, which confirmed that TREM-1 is regulated differently in primary human neutrophils and monocytes. In addition, we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner, which suggests that the clustering of TREM-1 on the membrane promotes its oligomerization. We further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and multimerization. TREM-1 multimerization at the cell surface is also mediated by its endogenous ligand, a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 multimerization. These results provide evidence for ligand-induced, receptor-mediated dimerization of TREM-1. Collectively, our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils.
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000143556 7001_ $$aBoufenzer, Amir$$b1
000143556 7001_ $$aJolly, Lucie$$b2
000143556 7001_ $$aLe Cordier, Helene$$b3
000143556 7001_ $$aWang, Guanbo$$b4
000143556 7001_ $$aHeck, Albert Jr$$b5
000143556 7001_ $$0P:(DE-He78)d2b4dd8bdffe4aaa0f5e30e91587766f$$aCerwenka, Adelheid$$b6$$udkfz
000143556 7001_ $$aVinolo, Emilie$$b7
000143556 7001_ $$aNazabal, Alexis$$b8
000143556 7001_ $$aKriznik, Alexandre$$b9
000143556 7001_ $$aLaunay, Pierre$$b10
000143556 7001_ $$aGibot, Sebastien$$b11
000143556 7001_ $$aDerive, Marc$$b12
000143556 773__ $$0PERI:(DE-600)2219471-X$$a10.1038/s41423-018-0003-5$$gVol. 16, no. 5, p. 460 - 472$$n5$$p460 - 472$$tCellular & molecular immunology$$v16$$x2042-0226$$y2019
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