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

Authors
  • Fong, David1
  • Grégoire-Gélinas, Pascal2
  • Cheng, Alexandre P2
  • Mezheritsky, Tal2
  • Lavertu, Marc2
  • Sato, Sachiko3
  • Hoemann, Caroline D4
  • 1 Institute of Biomedical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada. , (Canada)
  • 2 Department of Chemical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada. , (Canada)
  • 3 Research Centre for Infectious Diseases, Faculty of Medicine, Laval University, Quebec, QC, G1V 4G2, Canada. , (Canada)
  • 4 Institute of Biomedical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada; Department of Chemical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada; FRQ-S Biomedical Research Group/ Groupe de Recherche en Sciences et Technologies Biomédicales, École Polytechnique, Montreal, QC, H3T 1J4, Canada. Electronic address: [email protected] , (Canada)
Type
Published Article
Journal
Biomaterials
Publication Date
Jun 01, 2017
Volume
129
Pages
127–138
Identifiers
DOI: 10.1016/j.biomaterials.2017.03.022
PMID: 28340358
Source
Medline
Keywords
Language
English
License
Unknown

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 μg/mL, or activated the inflammasome to release IL-1β and PGE2 at 50-150 μg/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-β 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-1β. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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