Bibliographic Details
| Title: |
Bivalent Inhibitor with Selectivity for Trimeric MMP-9 Amplifies Neutrophil Chemotaxis and Enables Functional Studies on MMP-9 Proteoforms |
| Authors: |
Elisa Nuti, Armando Rossello, Doretta Cuffaro, Caterina Camodeca, Jens Van Bael, Dries van der Maat, Erik Martens, Pierre Fiten, Rafaela Vaz Sousa Pereira, Estefania Ugarte-Berzal, Mieke Gouwy, Ghislain Opdenakker, Jennifer Vandooren |
| Source: |
Cells, Vol 9, Iss 7, p 1634 (2020) |
| Publisher Information: |
MDPI AG, 2020. |
| Publication Year: |
2020 |
| Collection: |
LCC:Cytology |
| Subject Terms: |
MMP-9, inflammation, endotoxemia, leukocytosis, chemotaxis, sepsis, Cytology, QH573-671 |
| More Details: |
A fundamental part of the immune response to infection or injury is leukocyte migration. Matrix metalloproteinases (MMPs) are a class of secreted or cell-bound endopeptidases, implicated in every step of the process of inflammatory cell migration. Hence, specific inhibition of MMPs is an interesting approach to control inflammation. We evaluated the potential of a bivalent carboxylate inhibitor to selectively inhibit the trimeric proteoform of MMP-9 and compared this with a corresponding monovalent inhibitor. The bivalent inhibitor efficiently inhibited trimeric MMP-9 (IC50 = 0.1 nM), with at least 500-fold selectivity for MMP-9 trimers over monomers. Surprisingly, in a mouse model for chemotaxis, the bivalent inhibitor amplified leukocyte influxes towards lipopolysaccharide-induced inflammation. We verified by microscopic and flow cytometry analysis increased amounts of neutrophils. In a mouse model for endotoxin shock, mice treated with the bivalent inhibitor had significantly increased levels of MMP-9 in plasma and lungs, indicative for increased inflammation. In conclusion, we propose a new role for MMP-9 trimers in tempering excessive neutrophil migration. In addition, we have identified a small molecule inhibitor with a high selectivity for the trimeric proteoform of MMP-9, which will allow further research on the functions of MMP-9 proteoforms. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2073-4409 |
| Relation: |
https://www.mdpi.com/2073-4409/9/7/1634; https://doaj.org/toc/2073-4409 |
| DOI: |
10.3390/cells9071634 |
| Access URL: |
https://doaj.org/article/598faee1983745e0a58f6bed59c8b4c2 |
| Accession Number: |
edsdoj.598faee1983745e0a58f6bed59c8b4c2 |
| Database: |
Directory of Open Access Journals |
