Proteolytic Vesicles Derived from <i>Salmonella enterica</i> Serovar Typhimurium-Infected Macrophages: Enhancing MMP-9-Mediated Invasion and EV Accumulation
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
Affiliations
Alon Nudelman
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
Anjana Shenoy
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
Hyla Allouche-Arnon
Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel
Michal Fisler
Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel
Irit Rosenhek-Goldian
Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 7610001, Israel
Lior Dayan
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
Paula Abou Karam
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
Ziv Porat
Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel
Inna Solomonov
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
Neta Regev-Rudzki
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
Amnon Bar-Shir
Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel
Irit Sagi
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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 Salmonella enterica 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 S. 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 S. Typhimurium-infected macrophage-derived EVs, including the upregulation of MMP-9. The increased levels of MMP-9 observed in immune cells exposed to S. 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.