Lysosomal rupture induced by structurally distinct chitosans either promotes a type 1 IFN response or activates the inflammasome in macrophages.
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 PGE2at 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.
Institute of Biomedical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada.
David
D
Fong
Department of Chemical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada.
Pascal
P
Grégoire-Gélinas
Department of Chemical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada.
Alexandre P
AP
Cheng
Department of Chemical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada.
Tal
T
Mezheritsky
Department of Chemical Engineering, École Polytechnique, Montreal, QC, H3T 1J4, Canada.
Marc
M
Lavertu
Research Centre for Infectious Diseases, Faculty of Medicine, Laval University, Quebec, QC, G1V 4G2, Canada.
Sachiko
S
Sato
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: caroline.hoemann@polymtl.ca.
Caroline D
CD
Hoemann
D000107:Acetylation; D054377:Chemokine CXCL12 / Q000378:metabolism; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy; D020298:U937 Cells
D054377:Chemokine CXCL12; D058847:Inflammasomes; D007370:Interferon Type I; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D048271:Chitosan; D015232:Dinoprostone
Chitin/chitosan; Immunomodulation; Inflammasome; Macrophage; Type 1 interferon