Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response
BackgroundFetal inflammatory response mediated by the influx of immune cells and activation of pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is the major determinant of infection-associated preterm birth (PTB, live births < 37 weeks of gestation).ObjectiveTo red...
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1196453/full |
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| author | Ananth Kumar Kammala Angela Mosebarger Enkhtuya Radnaa Emma Rowlinson Natasha Vora Stephen J. Fortunato Surendra Sharma Melody Safarzadeh Ramkumar Menon |
| author_facet | Ananth Kumar Kammala Angela Mosebarger Enkhtuya Radnaa Emma Rowlinson Natasha Vora Stephen J. Fortunato Surendra Sharma Melody Safarzadeh Ramkumar Menon |
| author_sort | Ananth Kumar Kammala |
| collection | DOAJ |
| description | BackgroundFetal inflammatory response mediated by the influx of immune cells and activation of pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is the major determinant of infection-associated preterm birth (PTB, live births < 37 weeks of gestation).ObjectiveTo reduce the incidence of PTB by minimizing inflammation, extracellular vesicles (EVs) were electroporetically engineered to contain anti-inflammatory cytokine interleukin (IL)-10 (eIL-10), and their efficacy was tested in an ascending model of infection (vaginal administration of E. coli) induced PTB in mouse models.Study designEVs (size: 30-170 nm) derived from HEK293T cells were electroporated with recombinant IL-10 at 500 volts and 125 Ω, and 6 pulses to generate eIL-10. eIL-10 structural characters (electron microscopy, nanoparticle tracking analysis, ExoView [size and cargo content] and functional properties (co-treatment of macrophage cells with LPS and eIL-10) were assessed. To test efficacy, CD1 mice were vaginally inoculated with E. coli (1010CFU) and subsequently treated with either PBS, eIL-10 (500ng) or Gentamicin (10mg/kg) or a combination of eIL-10+gentamicin. Fetal inflammatory response in maternal and fetal tissues after the infection or treatment were conducted by suspension Cytometer Time of Flight (CyTOF) using a transgenic mouse model that express red fluorescent TdTomato (mT+) in fetal cells.ResultsEngineered EVs were structurally and functionally stable and showed reduced proinflammatory cytokine production from LPS challenged macrophage cells in vitro. Maternal administration of eIL-10 (10 µg/kg body weight) crossed feto-maternal barriers to delay E. coli-induced PTB to deliver live pups at term. Delay in PTB was associated with reduced feto-maternal uterine inflammation (immune cell infiltration and histologic chorioamnionitis, NF-κB activation, and proinflammatory cytokine production).ConclusionseIL-10 administration was safe, stable, specific, delayed PTB by over 72 hrs and delivered live pups. The delivery of drugs using EVs overcomes the limitations of in-utero fetal interventions. Protecting IL-10 in EVs eliminates the need for the amniotic administration of recombinant IL-10 for its efficacy. |
| first_indexed | 2024-03-12T17:33:43Z |
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| language | English |
| last_indexed | 2024-03-12T17:33:43Z |
| publishDate | 2023-08-01 |
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| spelling | doaj.art-747381e5500a456a9907fc1d4f6d1a132023-08-04T14:06:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.11964531196453Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory responseAnanth Kumar Kammala0Angela Mosebarger1Enkhtuya Radnaa2Emma Rowlinson3Natasha Vora4Stephen J. Fortunato5Surendra Sharma6Melody Safarzadeh7Ramkumar Menon8Division of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDivision of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDivision of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDivision of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDivision of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wexner Medical Center, The Ohio State University, Columbus, OH, United StatesDepartment of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI, United StatesDivision of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDivision of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesBackgroundFetal inflammatory response mediated by the influx of immune cells and activation of pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is the major determinant of infection-associated preterm birth (PTB, live births < 37 weeks of gestation).ObjectiveTo reduce the incidence of PTB by minimizing inflammation, extracellular vesicles (EVs) were electroporetically engineered to contain anti-inflammatory cytokine interleukin (IL)-10 (eIL-10), and their efficacy was tested in an ascending model of infection (vaginal administration of E. coli) induced PTB in mouse models.Study designEVs (size: 30-170 nm) derived from HEK293T cells were electroporated with recombinant IL-10 at 500 volts and 125 Ω, and 6 pulses to generate eIL-10. eIL-10 structural characters (electron microscopy, nanoparticle tracking analysis, ExoView [size and cargo content] and functional properties (co-treatment of macrophage cells with LPS and eIL-10) were assessed. To test efficacy, CD1 mice were vaginally inoculated with E. coli (1010CFU) and subsequently treated with either PBS, eIL-10 (500ng) or Gentamicin (10mg/kg) or a combination of eIL-10+gentamicin. Fetal inflammatory response in maternal and fetal tissues after the infection or treatment were conducted by suspension Cytometer Time of Flight (CyTOF) using a transgenic mouse model that express red fluorescent TdTomato (mT+) in fetal cells.ResultsEngineered EVs were structurally and functionally stable and showed reduced proinflammatory cytokine production from LPS challenged macrophage cells in vitro. Maternal administration of eIL-10 (10 µg/kg body weight) crossed feto-maternal barriers to delay E. coli-induced PTB to deliver live pups at term. Delay in PTB was associated with reduced feto-maternal uterine inflammation (immune cell infiltration and histologic chorioamnionitis, NF-κB activation, and proinflammatory cytokine production).ConclusionseIL-10 administration was safe, stable, specific, delayed PTB by over 72 hrs and delivered live pups. The delivery of drugs using EVs overcomes the limitations of in-utero fetal interventions. Protecting IL-10 in EVs eliminates the need for the amniotic administration of recombinant IL-10 for its efficacy.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1196453/fullpregnancyextracellular vesiclesascending infectionfetal membranesanti-inflammatoryantibiotics |
| spellingShingle | Ananth Kumar Kammala Angela Mosebarger Enkhtuya Radnaa Emma Rowlinson Natasha Vora Stephen J. Fortunato Surendra Sharma Melody Safarzadeh Ramkumar Menon Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response Frontiers in Immunology pregnancy extracellular vesicles ascending infection fetal membranes anti-inflammatory antibiotics |
| title | Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response |
| title_full | Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response |
| title_fullStr | Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response |
| title_full_unstemmed | Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response |
| title_short | Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response |
| title_sort | extracellular vesicles mediated recombinant il 10 protects against ascending infection associated preterm birth by reducing fetal inflammatory response |
| topic | pregnancy extracellular vesicles ascending infection fetal membranes anti-inflammatory antibiotics |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1196453/full |
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