David Fong, Pascal Gregoire-Gelinas, Alexandre P. Cheng, Tal Mezheritsky, Marc Lavertu, Sachiko Sato and Caroline D. Hoemann
Article (2017)
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Published Version Terms of Use: Creative Commons Attribution . Download (1MB) |
Cite this document: | Fong, D., Gregoire-Gelinas, P., Cheng, A. P., Mezheritsky, T., Lavertu, M., Sato, S. & Hoemann, C. D. (2017). Lysosomal rupture induced by structurally distinct chitosans either promotes a type 1 IFN response or activates the inflammasome in macrophages. Biomaterials, 129, p. 127-138. doi:10.1016/j.biomaterials.2017.03.022 |
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Abstract
Chitosan is a family of glucosamine and N-acetyl glucosamine polysaccharides with poorly understood immune modulating properties. Here, functional U937 macrophage responses were analyzed in response to a novel library of twenty chitosans with controlled degree of deacetylation (DDA, 60-98%), molecular weight (1 to >100 kDa), and acetylation pattern (block vs. random). Specific chitosan preparations (10 or 190 kDa 80% block DDA and 3, 5, or 10 kDa 98% DDA) either induced macrophages to release CXCL10 and IL-1ra at 5-50 mug/mL, or activated the inflammasome to release IL-1beta and PGE2 at 50-150 mug/mL. Chitosan induction of these factors required lysosomal acidification. CXCL10 production was preceded by lysosomal rupture as shown by time-dependent co-localization of galectin-3 and chitosan and slowed autophagy flux, and specifically depended on IFN-beta paracrine activity and STAT-2 activation that could be suppressed by PGE2. Chitosan induced a type I IFN paracrine response or inflammasome response depending on the extent of lysosomal rupture and cytosolic foreign body invasion. This study identifies the structural motifs that lead to chitosan-driven cytokine responses in macrophages and indicates that lysosomal rupture is a key mechanism that determines the endogenous release of either IL-1ra or IL-1beta.
Uncontrolled Keywords
Acetylation; Chemokine CXCL12/metabolism; Chitosan/chemistry/*pharmacology; Dinoprostone/metabolism; Humans; Inflammasomes/*metabolism; Interferon Type I/*metabolism; Interleukin 1 Receptor Antagonist Protein/metabolism; Interleukin-1beta/metabolism; Lysosomes/drug effects/*pathology; Macrophages/drug effects/*metabolism; Proton Magnetic Resonance Spectroscopy; U937 Cells; *Chitin/chitosan; *Immunomodulation; *Inflammasome; *Macrophage; *Type 1 interferon
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Subjects: |
1800 Génie chimique > 1800 Génie chimique 1800 Génie chimique > 1802 Génie biochimique 1900 Génie biomédical > 1900 Génie biomédical |
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Department: |
Département de génie chimique Institut de génie biomédical |
Research Center: | GRSTB - Centre de recherche en sciences et technologies biomédicales |
Funders: | Canadian Institutes of Health Research, Fonds de recherche du Quebec - Sante, Fonds de recherche du Quebec - Nature et technologies, CRSNG / NSERC Summer Scholarship |
Grant number: | MOP 303615-BME, 22341 |
Date Deposited: | 16 Aug 2021 15:04 |
Last Modified: | 17 Aug 2021 01:20 |
PolyPublie URL: | https://publications.polymtl.ca/4868/ |
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Journal Title: | Biomaterials (vol. 129) |
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Publisher: | Elsevier |
Official URL: | https://doi.org/10.1016/j.biomaterials.2017.03.022 |
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