Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 12, Pages 5943-5951Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301695
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Funding
- National Institutes of Health [R21 AI093302, RO1 AI025780, RO1 AI072195, RO1 HL112671, T32 AI095213]
- National Science Foundation [1022336]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [1022336] Funding Source: National Science Foundation
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Chitosan, the deacetylated derivative of chitin, can be found in the cell wall of some fungi and is used in translational applications. We have shown that highly purified preparations of chitosan, but not chitin, activate the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in primed mouse bone marrow-derived macrophages (BMMF), inducing a robust IL-1b response. In this article, we further define specific cell types that are activated and delineate mechanisms of activation. BMMF differentiated to promote a classically activated (M1) phenotype released more IL-1b in response to chitosan than intermediate or alternatively activated macrophages (M2). Chitosan, but not chitin, induced a robust IL-1b response in mouse dendritic cells, peritoneal macrophages, and human PBMCs. Three mechanisms for NLRP3 inflammasome activation may contribute: K+ efflux, reactive oxygen species, and lysosomal destabilization. The contributions of these mechanisms were tested using a K+ efflux inhibitor, high extracellular potassium, a mitochondrial reactive oxygen species inhibitor, lysosomal acidification inhibitors, and a cathepsin B inhibitor. These studies revealed that each of these pathways participated in optimal NLRP3 inflammasome activation by chitosan. Finally, neither chitosan nor chitin stimulated significant release from unprimed BMM phi of any of 22 cytokines and chemokines assayed. This study has the following conclusions: 1) chitosan, but not chitin, stimulates IL-1b release from multiple murine and human cell types; 2) multiple nonredundant mechanisms appear to participate in inflammasome activation by chitosan; and 3) chitin and chitosan are relatively weak stimulators of inflammatory mediators from unprimed BMMF. These data have implications for understanding the nature of the immune response to microbes and biomaterials that contain chitin and chitosan.
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