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Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions
BACKGROUND: Chemokine therapy with C–C motif chemokine ligand 25 (CCL25) is currently under investigation as a promising approach to treat articular cartilage degeneration. We developed a delayed release mechanism based on Poly (lactic-co-glycolic acid) (PLGA) microparticle encapsulation for intraar...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992824/ https://www.ncbi.nlm.nih.gov/pubmed/33766057 http://dx.doi.org/10.1186/s12951-021-00830-7 |
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author | Spinnen, J. Fröhlich, K. Sinner, N. Stolk, M. Ringe, J. Shopperly, L. Sittinger, M. Dehne, T. Seifert, M. |
author_facet | Spinnen, J. Fröhlich, K. Sinner, N. Stolk, M. Ringe, J. Shopperly, L. Sittinger, M. Dehne, T. Seifert, M. |
author_sort | Spinnen, J. |
collection | PubMed |
description | BACKGROUND: Chemokine therapy with C–C motif chemokine ligand 25 (CCL25) is currently under investigation as a promising approach to treat articular cartilage degeneration. We developed a delayed release mechanism based on Poly (lactic-co-glycolic acid) (PLGA) microparticle encapsulation for intraarticular injections to ensure prolonged release of therapeutic dosages. However, CCL25 plays an important role in immune cell regulation and inflammatory processes like T-cell homing and chronic tissue inflammation. Therefore, the potential of CCL25 to activate immune cells must be assessed more thoroughly before further translation into clinical practice. The aim of this study was to evaluate the reaction of different immune cell subsets upon stimulation with different dosages of CCL25 in comparison to CCL25 released from PLGA particles. RESULTS: Immune cell subsets were treated for up to 5 days with CCL25 and subsequently analyzed regarding their cytokine secretion, surface marker expression, polarization, and migratory behavior. The CCL25 receptor C–C chemokine receptor type 9 (CCR9) was expressed to a different extent on all immune cell subsets. Direct stimulation of peripheral blood mononuclear cells (PBMCs) with high dosages of CCL25 resulted in strong increases in the secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-1β (IL-1β), tumor-necrosis-factor-α (TNF-α) and interferon-γ (IFN-γ), upregulation of human leukocyte antigen-DR (HLA-DR) on monocytes and CD4(+) T-cells, as well as immune cell migration along a CCL25 gradient. Immune cell stimulation with the supernatants from CCL25 loaded PLGA microparticles caused moderate increases in MCP-1, IL-8, and IL-1β levels, but no changes in surface marker expression or migration. Both CCL25-loaded and unloaded PLGA microparticles induced an increase in IL-8 and MCP-1 release in PBMCs and macrophages, and a slight shift of the surface marker profile towards the direction of M2-macrophage polarization. CONCLUSIONS: While supernatants of CCL25 loaded PLGA microparticles did not provoke strong inflammatory reactions, direct stimulation with CCL25 shows the critical potential to induce global inflammatory activation of human leukocytes at certain concentrations. These findings underline the importance of a safe and reliable release system in a therapeutic setup. Failure of the delivery system could result in strong local and systemic inflammatory reactions that could potentially negate the benefits of chemokine therapy. [Image: see text] |
format | Online Article Text |
id | pubmed-7992824 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-79928242021-03-25 Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions Spinnen, J. Fröhlich, K. Sinner, N. Stolk, M. Ringe, J. Shopperly, L. Sittinger, M. Dehne, T. Seifert, M. J Nanobiotechnology Research BACKGROUND: Chemokine therapy with C–C motif chemokine ligand 25 (CCL25) is currently under investigation as a promising approach to treat articular cartilage degeneration. We developed a delayed release mechanism based on Poly (lactic-co-glycolic acid) (PLGA) microparticle encapsulation for intraarticular injections to ensure prolonged release of therapeutic dosages. However, CCL25 plays an important role in immune cell regulation and inflammatory processes like T-cell homing and chronic tissue inflammation. Therefore, the potential of CCL25 to activate immune cells must be assessed more thoroughly before further translation into clinical practice. The aim of this study was to evaluate the reaction of different immune cell subsets upon stimulation with different dosages of CCL25 in comparison to CCL25 released from PLGA particles. RESULTS: Immune cell subsets were treated for up to 5 days with CCL25 and subsequently analyzed regarding their cytokine secretion, surface marker expression, polarization, and migratory behavior. The CCL25 receptor C–C chemokine receptor type 9 (CCR9) was expressed to a different extent on all immune cell subsets. Direct stimulation of peripheral blood mononuclear cells (PBMCs) with high dosages of CCL25 resulted in strong increases in the secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-1β (IL-1β), tumor-necrosis-factor-α (TNF-α) and interferon-γ (IFN-γ), upregulation of human leukocyte antigen-DR (HLA-DR) on monocytes and CD4(+) T-cells, as well as immune cell migration along a CCL25 gradient. Immune cell stimulation with the supernatants from CCL25 loaded PLGA microparticles caused moderate increases in MCP-1, IL-8, and IL-1β levels, but no changes in surface marker expression or migration. Both CCL25-loaded and unloaded PLGA microparticles induced an increase in IL-8 and MCP-1 release in PBMCs and macrophages, and a slight shift of the surface marker profile towards the direction of M2-macrophage polarization. CONCLUSIONS: While supernatants of CCL25 loaded PLGA microparticles did not provoke strong inflammatory reactions, direct stimulation with CCL25 shows the critical potential to induce global inflammatory activation of human leukocytes at certain concentrations. These findings underline the importance of a safe and reliable release system in a therapeutic setup. Failure of the delivery system could result in strong local and systemic inflammatory reactions that could potentially negate the benefits of chemokine therapy. [Image: see text] BioMed Central 2021-03-25 /pmc/articles/PMC7992824/ /pubmed/33766057 http://dx.doi.org/10.1186/s12951-021-00830-7 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Spinnen, J. Fröhlich, K. Sinner, N. Stolk, M. Ringe, J. Shopperly, L. Sittinger, M. Dehne, T. Seifert, M. Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions |
title | Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions |
title_full | Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions |
title_fullStr | Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions |
title_full_unstemmed | Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions |
title_short | Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions |
title_sort | therapies with ccl25 require controlled release via microparticles to avoid strong inflammatory reactions |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992824/ https://www.ncbi.nlm.nih.gov/pubmed/33766057 http://dx.doi.org/10.1186/s12951-021-00830-7 |
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