Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation
Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of cir...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-01-01
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| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/20013078.2019.1706708 |
| _version_ | 1819109756930883584 |
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| author | Kieran P. O’Dea Ying Ying Tan Sneh Shah Brijesh V Patel Kate C Tatham Mike R. Wilson Sanooj Soni Masao Takata |
| author_facet | Kieran P. O’Dea Ying Ying Tan Sneh Shah Brijesh V Patel Kate C Tatham Mike R. Wilson Sanooj Soni Masao Takata |
| author_sort | Kieran P. O’Dea |
| collection | DOAJ |
| description | Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation. |
| first_indexed | 2024-12-22T03:30:53Z |
| format | Article |
| id | doaj.art-8af85ed349d2405f8670d4761a8c6660 |
| institution | Directory Open Access Journal |
| issn | 2001-3078 |
| language | English |
| last_indexed | 2024-12-22T03:30:53Z |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj.art-8af85ed349d2405f8670d4761a8c66602022-12-21T18:40:31ZengWileyJournal of Extracellular Vesicles2001-30782020-01-019110.1080/20013078.2019.17067081706708Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammationKieran P. O’Dea0Ying Ying Tan1Sneh Shah2Brijesh V Patel3Kate C Tatham4Mike R. Wilson5Sanooj Soni6Masao Takata7Chelsea & Westminster HospitalChelsea & Westminster HospitalChelsea & Westminster HospitalChelsea & Westminster HospitalChelsea & Westminster HospitalChelsea & Westminster HospitalChelsea & Westminster HospitalChelsea & Westminster HospitalMicrovesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation.http://dx.doi.org/10.1080/20013078.2019.1706708extracellular vesiclesmicrovesiclesmonocytessystemic inflammationpulmonary vasculature |
| spellingShingle | Kieran P. O’Dea Ying Ying Tan Sneh Shah Brijesh V Patel Kate C Tatham Mike R. Wilson Sanooj Soni Masao Takata Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation Journal of Extracellular Vesicles extracellular vesicles microvesicles monocytes systemic inflammation pulmonary vasculature |
| title | Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation |
| title_full | Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation |
| title_fullStr | Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation |
| title_full_unstemmed | Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation |
| title_short | Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation |
| title_sort | monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low grade systemic inflammation |
| topic | extracellular vesicles microvesicles monocytes systemic inflammation pulmonary vasculature |
| url | http://dx.doi.org/10.1080/20013078.2019.1706708 |
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