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Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors.

Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors.
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Weiss G, Lai C, Fife ME, Grabiec AM, Tildy B, Snelgrove RJ, Xin G, Lloyd CM, Hussell T,


Weiss G, Lai C, Fife ME, Grabiec AM, Tildy B, Snelgrove RJ, Xin G, Lloyd CM, Hussell T, (click to view)

Weiss G, Lai C, Fife ME, Grabiec AM, Tildy B, Snelgrove RJ, Xin G, Lloyd CM, Hussell T,

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Mucosal immunology 2016 12 14() doi 10.1038/mi.2016.104

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on neutrophils and monocyte/macrophages and amplifies Toll-like receptor-mediated inflammation during infection. TREM-1 also exists in an antagonistic soluble form (sTREM-1) that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane-bound and sTREM-1 in polygenic infections is currently unknown. In a mouse co-infection model where preceding viral infection greatly enhances bacteria co-infection, we now determine a mechanisms for the striking increase in sTREM-1 and the loss of TREM-1 on surface of neutrophils. We identified a matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. Intriguingly, MMP-9 inhibition significantly reduces bacterial load and ensuing immunopathology in a co-infection model. This highlights MMP-9 inhibition as a potential therapeutic via blocking cleavage of TREM-1.Mucosal Immunology advance online publication 14 December 2016. doi:10.1038/mi.2016.104.

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