Sci. Signal., 8 September 2009
Immunology Tissue Damage Sensor
L. Bryan Ray
Science, Science Signaling, AAAS, Washington, DC 20005, USA
Babelova et al. report that the proteoglycan biglycan may serve as a signal from injured tissue to activate inflammatory responses. Although its solubilization is not well characterized, normally stationary biglycan molecules appear to be released from the extracellular matrix in soluble form after tissue injury or when the molecule is secreted from macrophages. In cultures of primary mouse macrophages, treatment with biglycan stimulated secretion of interleukin-1β (IL-1β) and activated the NLRP3 [nod-like receptor (NLR) family, pyrin domain containing 3, also called Nalp3] inflammasome complex that leads to activation of caspase-1, cleavage of pro-IL-1β, and consequent inflammation. Biglycan has been reported to interact with NLRs, but studies with pharmacological inhibitors and macrophages lacking the purinergic receptors for ATP showed that P2X7 and P2X4 were also required for the effects of biglycan. Biglycan could also be crosslinked to these receptors and immunoprecipitated. Immunoprecipitation of the purinergic receptors revealed that TLRs were co-immunoprecipitated only if biglucan was present, leading the authors to propose that biglycan may link the two receptors, both of which are key elements of inflammatory signaling. Animals genetically deficient in production of biglycan had blunted inflammatory responses both to a stimulus mimicking infection (treatment with lipopolysaccharide) and to a renal injury protocol that models inflammation not triggered by an infectious agent. Babelova et al. argue that, together, their results implicate biglycan as a danger signal from the extracellular matrix that allows activation of the innate immune system in response to tissue damage.
A. Babelova, K. Moreth, W. Tsalastra-Greul, J. Zeng-Brouwers, O. Eickelberg, M. F. Young, P. Bruckner, J. Pfeilschifter, R. M. Schaefer, H.-J. Gröne, L. Schaefer, Biglycan, a danger signal that activates the NLRP3 inflammasome via Toll-like and P2X receptors. J. Biol. Chem. 284, 24035–24048 (2009). [PubMed]
Citation: L. B. Ray, Tissue Damage Sensor. Sci. Signal. 2, ec301 (2009).
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