(1,3)-beta-glucans activate both dectin-1 and NLRP3 inflammasome in human macrophages.
beta-Glucans are naturally occurring polysaccharides that are the major cell wall components of fungi. Recognition of beta-glucans is mediated through a membrane-bound pattern recognition receptor called dectin-1, and gene knock-out studies have shown that dectin-1 plays an important role in antifungal immune response in vivo. In this report, we have studied the effect of large particulate (1,3)-beta-glucans, including curdlan, glucan from baker's yeast, paramylon, and zymosan, on inflammatory response in human macrophages. We show that beta-glucans activate the transcription of the proinflammatory cytokine IL-1beta through a dectin-1-dependent pathway in human macrophages. Moreover, dectin-1 receptor associated Syk tyrosine kinase was essential for beta-glucan induced IL-1beta mRNA expression. In contrast to LPS, beta-glucans also strongly activated the secretion of IL-1beta. This beta-glucan triggered IL-1beta release was abolished by cytochalasin D, an inhibitor of phagocytosis, demonstrating that cytosolic recognition of beta-glucans is required for IL-1beta response in human macrophages. RNA interference-mediated gene knockdown experiments demonstrated that cytoplasmic NLRP3 inflammasome is essential for beta-glucan-induced IL-1beta secretion. Moreover, our results suggest that beta-glucan-induced NLRP3 inflammasome activation is dependent on the dectin-1/Syk signaling pathway. Furthermore, our results suggest that the lysosomal cathepsin B protease, the formation of reactive oxygen species, and the efflux of potassium are needed for beta-glucan-induced NLRP3 inflammasome activation. In conclusion, our results show that beta-glucans are recognized by membrane-associated dectin-1 and cytoplasmic NLRP3 inflammasome resulting in IL-1beta gene transcription and IL-1beta secretion in human macrophages, respectively.
Kankkunen
Päivi
P
Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
Teirilä
Laura
L
Rintahaka
Johanna
J
Alenius
Harri
H
Wolff
Henrik
H
Matikainen
Sampsa
S
D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005656:Fungal Proteins / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D037181:Lectins, C-Type; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D047071:beta-Glucans / Q000276:immunology* / Q000378:metabolism; D000099181:Dectin-1
D002352:Carrier Proteins; D005656:Fungal Proteins; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; D047071:beta-Glucans; D000099181:Dectin-1; C453881:NLRP3 protein, human