期刊
MUCOSAL IMMUNOLOGY
卷 10, 期 4, 页码 1021-1030出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2016.104
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资金
- M.R.C. & Asthma UK Centre in Allergic Mechanisms of Asthma
- GlaxoSmithKline
- AstraZeneca
- MRC [MC_PC_12015, G0802752] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre, MRC-Asthma UK Centre, AUK-IG-2014-286] Funding Source: researchfish
- Medical Research Council [G1000758B, G0802752, G1000758, MC_PC_12015] Funding Source: researchfish
- Wellcome Trust [202865/Z/16/Z] Funding Source: researchfish
- Wellcome Trust [202865/Z/16/Z] Funding Source: Wellcome Trust
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.
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