Abstract
The role of endogenous inducers of inflammation is poorly understood. To produce the proinflammatory master cytokine interleukin (IL)-1beta, macrophages need double stimulation with ligands to both Toll-like receptors (TLRs) for IL-1beta gene transcription and nucleotide-binding oligomerization domain-like receptors for activation of the inflammasome. It is particularly intriguing to define how this complex regulation is mediated in the absence of an infectious trigger. Biglycan, a ubiquitous leucine-rich repeat proteoglycan of the extracellular matrix, interacts with TLR2/4 on macrophages. The objective of this study was to define the role of biglycan in the synthesis and activation of IL-1beta. Here we show that in macrophages, soluble biglycan induces the NLRP3/ASC inflammasome, activating caspase-1 and releasing mature IL-1beta without the need for additional costimulatory factors. This is brought about by the interaction of biglycan with TLR2/4 and purinergic P2X(4)/P2X(7) receptors, which induces receptor cooperativity. Furthermore, reactive oxygen species formation is involved in biglycan-mediated activation of the inflammasome. By signaling through TLR2/4, biglycan stimulates the expression of NLRP3 and pro-IL-1beta mRNA. Both in a model of non-infectious inflammatory renal injury (unilateral ureteral obstruction) and in lipopolysaccharide-induced sepsis, biglycan-deficient mice displayed lower levels of active caspase-1 and mature IL-1beta in the kidney, lung, and circulation. Our results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and describe a fundamental paradigm of how tissue stress or injury is monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biglycan
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Carrier Proteins / biosynthesis*
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspase 1 / metabolism
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Extracellular Matrix / genetics
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Extracellular Matrix / immunology
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Extracellular Matrix / metabolism
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / immunology
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Extracellular Matrix Proteins / metabolism*
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Kidney / immunology
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Kidney / metabolism
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Lung / immunology
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Lung / metabolism
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Macrophages / immunology
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Macrophages / metabolism*
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Male
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Mice
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Mice, Knockout
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Structure, Tertiary / genetics
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Proteoglycans / genetics
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Proteoglycans / immunology
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Proteoglycans / metabolism*
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Receptors, Purinergic P2 / genetics
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Receptors, Purinergic P2 / immunology
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Receptors, Purinergic P2 / metabolism*
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Receptors, Purinergic P2X4
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Receptors, Purinergic P2X7
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Signal Transduction*
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 2 / metabolism*
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism*
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Ureteral Obstruction / genetics
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Ureteral Obstruction / immunology
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Ureteral Obstruction / metabolism
Substances
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Bgn protein, mouse
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Biglycan
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Carrier Proteins
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Extracellular Matrix Proteins
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Interleukin-1beta
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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P2rx4 protein, mouse
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P2rx7 protein, mouse
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Proteoglycans
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Receptors, Purinergic P2
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Receptors, Purinergic P2X4
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Receptors, Purinergic P2X7
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Caspase 1