Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors.
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.
Babelova
Andrea
A
Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, 60590 Frankfurt am Main, Germany.
Moreth
Kristin
K
Tsalastra-Greul
Wasiliki
W
Zeng-Brouwers
Jinyang
J
Eickelberg
Oliver
O
Young
Marian F
MF
Bruckner
Peter
P
Pfeilschifter
Josef
J
Schaefer
Roland M
RM
Gröne
Hermann-Josef
HJ
Schaefer
Liliana
L
D000818:Animals; D058578:Biglycan; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017434:Protein Structure, Tertiary / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C546885:Bgn protein, mouse; D058578:Biglycan; D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C548227:P2rx4 protein, mouse; C546469:P2rx7 protein, mouse; D011509:Proteoglycans; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020170:Caspase 1