{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:01:13Z","timestamp":1792112473623,"version":"4.4.0"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T00:00:00Z","timestamp":1594080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004497","name":"Onderzoeksraad, KU Leuven","doi-asserted-by":"publisher","award":["C16\/17\/010"],"award-info":[{"award-number":["C16\/17\/010"]}],"id":[{"id":"10.13039\/501100004497","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G0A3820N"],"award-info":[{"award-number":["G0A3820N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["12Z0920N"],"award-info":[{"award-number":["12Z0920N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007514","name":"Universit\u00e0 di Pisa","doi-asserted-by":"publisher","award":["PRA_2018_20"],"award-info":[{"award-number":["PRA_2018_20"]}],"id":[{"id":"10.13039\/501100007514","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells9071634","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T10:41:09Z","timestamp":1594118469000},"page":"1634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Bivalent Inhibitor with Selectivity for Trimeric MMP-9 Amplifies Neutrophil Chemotaxis and Enables Functional Studies on MMP-9 Proteoforms"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5376","authenticated-orcid":false,"given":"Elisa","family":"Nuti","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-8091","authenticated-orcid":false,"given":"Armando","family":"Rossello","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doretta","family":"Cuffaro","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8676-7311","authenticated-orcid":false,"given":"Caterina","family":"Camodeca","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Van Bael","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dries","family":"van der Maat","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Martens","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Fiten","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela Vaz Sousa","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Ugarte-Berzal","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke","family":"Gouwy","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1714-2294","authenticated-orcid":false,"given":"Ghislain","family":"Opdenakker","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7157-3370","authenticated-orcid":false,"given":"Jennifer","family":"Vandooren","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. 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