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Lysosomal rupture induced by structurally distinct chitosans either promotes a type 1 IFN response or activates the inflammasome in macrophages

David Fong, Pascal Gregoire-Gelinas, Alexandre P. Cheng, Tal Mezheritsky, Marc Lavertu, Sachiko Sato and Caroline D. Hoemann

Article (2017)

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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

Subjects: 1800 Chemical engineering > 1800 Chemical engineering
1800 Chemical engineering > 1802 Biochemical engineering
1900 Biomedical engineering > 1900 Biomedical engineering
Department: Department of Chemical Engineering
Institut de génie biomédical
Research Center: GRSTB - Biomedical Science and Technologies Research Centre
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
PolyPublie URL: https://publications.polymtl.ca/4868/
Journal Title: Biomaterials (vol. 129)
Publisher: Elsevier
DOI: 10.1016/j.biomaterials.2017.03.022
Official URL: https://doi.org/10.1016/j.biomaterials.2017.03.022
Date Deposited: 16 Aug 2021 15:04
Last Modified: 09 Apr 2024 01:16
Cite in APA 7: 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, 127-138. https://doi.org/10.1016/j.biomaterials.2017.03.022


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