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@ARTICLE{Carrasco:143556,
author = {K. Carrasco and A. Boufenzer and L. Jolly and H. Le Cordier
and G. Wang and A. J. Heck and A. Cerwenka$^*$ and E. Vinolo
and A. Nazabal and A. Kriznik and P. Launay and S. Gibot and
M. Derive},
title = {{TREM}-1 multimerization is essential for its activation on
monocytes and neutrophils.},
journal = {Cellular $\&$ molecular immunology},
volume = {16},
number = {5},
issn = {2042-0226},
address = {London [u.a.]},
publisher = {Nature Publ. Group},
reportid = {DKFZ-2019-01137},
pages = {460 - 472},
year = {2019},
abstract = {The 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.},
cin = {D080},
ddc = {610},
cid = {I:(DE-He78)D080-20160331},
pnm = {314 - Tumor immunology (POF3-314)},
pid = {G:(DE-HGF)POF3-314},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29568119},
doi = {10.1038/s41423-018-0003-5},
url = {https://inrepo02.dkfz.de/record/143556},
}