The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
Biglycan, a Danger Signal That Activates the NLRP3 Inflammasome via Toll-like and P2X Receptors
Open accessAbstract
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.
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Cites
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Cited by
The NLRP3 inflammasome: molecular activation and regulation to therapeutics
Swanson, K. V., Deng, M., & Ting, J. P.-Y. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0165-0 · Cited by 4,884
Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051
Extracellular matrix structure
Theocharis, A. D., Skandalis, S. S., Gialeli, C., & Karamanos, N. K. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.11.001 · Cited by 2,598
Concepts of extracellular matrix remodelling in tumour progression and metastasis
Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J., & Werb, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-18794-x · Cited by 2,296
DAMP-sensing receptors in sterile inflammation and inflammatory diseases
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Metadata
- Authors
- Babelova, A., Moreth, K., Tsalastra-Greul, W., Zeng-Brouwers, J., Eickelberg, O., Young, M. F., Bruckner, P., Pfeilschifter, J., Schaefer, R. M., Gröne, H.-J., & Schaefer, L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 284
- Issue
- 36
- Pages
- 24035-24048
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2001244523
- Cited by
- 474
- References
- 17
- FWCI
- 13.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Babelova, A., Moreth, K., Tsalastra-Greul, W., Zeng-Brouwers, J., Eickelberg, O., Young, M. F., Bruckner, P., Pfeilschifter, J., Schaefer, R. M., Gröne, H.-J., & Schaefer, L. (2009). Biglycan, a Danger Signal That Activates the NLRP3 Inflammasome via Toll-like and P2X Receptors. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m109.014266
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