Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation
Proteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to <i>Salmone...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/12/2/434 |
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| author | Alon Nudelman Anjana Shenoy Hyla Allouche-Arnon Michal Fisler Irit Rosenhek-Goldian Lior Dayan Paula Abou Karam Ziv Porat Inna Solomonov Neta Regev-Rudzki Amnon Bar-Shir Irit Sagi |
| author_facet | Alon Nudelman Anjana Shenoy Hyla Allouche-Arnon Michal Fisler Irit Rosenhek-Goldian Lior Dayan Paula Abou Karam Ziv Porat Inna Solomonov Neta Regev-Rudzki Amnon Bar-Shir Irit Sagi |
| author_sort | Alon Nudelman |
| collection | DOAJ |
| description | Proteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to <i>Salmonella enterica</i> serovar Typhimurium infection. Specifically, we used global proteomics, in vitro, and in vivo approaches to investigate the composition and function of these proteolytic EVs. Using a model of <i>S.</i> Typhimurium infection in murine macrophages, we isolated and characterized a population of small EVs. Bulk proteomics analysis revealed significant changes in protein cargo of naïve and <i>S.</i> Typhimurium-infected macrophage-derived EVs, including the upregulation of MMP-9. The increased levels of MMP-9 observed in immune cells exposed to <i>S.</i> Typhimurium were found to be regulated by the toll-like receptor 4 (TLR-4)-mediated response to bacterial lipopolysaccharide. Macrophage-derived EV-associated MMP-9 enhanced the macrophage invasion through Matrigel as selective inhibition of MMP-9 reduced macrophage invasion. Systemic administration of fluorescently labeled EVs into immunocompromised mice demonstrated that EV-associated MMP activity facilitated increased accumulation of EVs in spleen and liver tissues. This study suggests that macrophages secrete proteolytic EVs to enhance invasion and ECM remodeling during bacterial infections, shedding light on an essential aspect of the immune response. |
| first_indexed | 2024-03-07T22:40:56Z |
| format | Article |
| id | doaj.art-b0a5d6ff48364c648a48f59bc6e7c9ef |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-07T22:40:56Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-b0a5d6ff48364c648a48f59bc6e7c9ef2024-02-23T15:08:49ZengMDPI AGBiomedicines2227-90592024-02-0112243410.3390/biomedicines12020434Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV AccumulationAlon Nudelman0Anjana Shenoy1Hyla Allouche-Arnon2Michal Fisler3Irit Rosenhek-Goldian4Lior Dayan5Paula Abou Karam6Ziv Porat7Inna Solomonov8Neta Regev-Rudzki9Amnon Bar-Shir10Irit Sagi11Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Chemical Research Support, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, IsraelLife Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, IsraelDepartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, IsraelProteolysis of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a crucial role in the immune response to bacterial infections. Here we report the secretion of MMPs associated with proteolytic extracellular vesicles (EVs) released by macrophages in response to <i>Salmonella enterica</i> serovar Typhimurium infection. Specifically, we used global proteomics, in vitro, and in vivo approaches to investigate the composition and function of these proteolytic EVs. Using a model of <i>S.</i> Typhimurium infection in murine macrophages, we isolated and characterized a population of small EVs. Bulk proteomics analysis revealed significant changes in protein cargo of naïve and <i>S.</i> Typhimurium-infected macrophage-derived EVs, including the upregulation of MMP-9. The increased levels of MMP-9 observed in immune cells exposed to <i>S.</i> Typhimurium were found to be regulated by the toll-like receptor 4 (TLR-4)-mediated response to bacterial lipopolysaccharide. Macrophage-derived EV-associated MMP-9 enhanced the macrophage invasion through Matrigel as selective inhibition of MMP-9 reduced macrophage invasion. Systemic administration of fluorescently labeled EVs into immunocompromised mice demonstrated that EV-associated MMP activity facilitated increased accumulation of EVs in spleen and liver tissues. This study suggests that macrophages secrete proteolytic EVs to enhance invasion and ECM remodeling during bacterial infections, shedding light on an essential aspect of the immune response.https://www.mdpi.com/2227-9059/12/2/434extracellular matrix<i>S.</i> Typhimuriumextracellular vesiclesmatrix metalloproteinasesMMP-9macrophages |
| spellingShingle | Alon Nudelman Anjana Shenoy Hyla Allouche-Arnon Michal Fisler Irit Rosenhek-Goldian Lior Dayan Paula Abou Karam Ziv Porat Inna Solomonov Neta Regev-Rudzki Amnon Bar-Shir Irit Sagi Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation Biomedicines extracellular matrix <i>S.</i> Typhimurium extracellular vesicles matrix metalloproteinases MMP-9 macrophages |
| title | Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation |
| title_full | Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation |
| title_fullStr | Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation |
| title_full_unstemmed | Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation |
| title_short | Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation |
| title_sort | proteolytic vesicles derived from i salmonella enterica i serovar typhimurium infected macrophages enhancing mmp 9 mediated invasion and ev accumulation |
| topic | extracellular matrix <i>S.</i> Typhimurium extracellular vesicles matrix metalloproteinases MMP-9 macrophages |
| url | https://www.mdpi.com/2227-9059/12/2/434 |
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