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Editorial
. 2015 Jun;67(6):1419-23.
doi: 10.1002/art.39102.

Editorial: Can GPR43 Sensing of Short-Chain Fatty Acids Unchain Inflammasome-Driven Arthritis?

Alexander Haslberger  1 , Robert Terkeltaub  2
Affiliations
Editorial

Editorial: Can GPR43 Sensing of Short-Chain Fatty Acids Unchain Inflammasome-Driven Arthritis?

Alexander Haslberger et al. Arthritis Rheumatol. 2015 Jun.
No abstract available

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Conflict of interest statement

Competing interests: Dr. Terkeltaub has served as a consultant to ARDEA/Astra-Zeneca, Takeda, REVIVE, and Relburn.

Figures

Figure 1
Figure 1. Leukocyte sensing of gut microbiota fermentation-derived SCFAs has paradoxical effects on inflammatory responses in mononuclear phagocytes
Panel A schematically illustrates that sensing of the gut microbiota fermentation-generated SCFAs actetate, butyrate, and propionate, via G protein receptor coupled GPR43, signaling limits multiple inflammatory responses by suppressing adhesion molecule and inflammatory mediator expression, and leukocyte survival and chemotaxis. These gut microbiota fermentation-derived SCFAs act in part by inhibiting transcriptional NF-κB signaling, and at relatively high concentrations, butyrate suppresses class I histone deacetylases. An open question is how gut microbiota-generated butyrate NLRP3 anti-inflammatory effects potentially relate to those of the transportable ketone body β-hydroxybutyrate (BHB), generated primarily by hepatic mitochondrial fatty acid oxidation, and a broad suppressor of NLRP3 inflammasome-driven disorders, as discussed in the text but not depicted here. Panel B highlights paradoxical findings, in which GPR43 sensing of gut microbiota fermentation-derived SCFAs has the potential to unleash acute inflammatory arthritis driven by NLRP3 inflammasome-induced IL-1β maturation and release in macrophage lineage, exemplified by the urate crystal-induced model acute gouty arthritis in new work of Vieira et al published in this issue of the journal (10). Here, GPR43 sensing of acetate provides a complementary set of priming signals to C5a (generated by C5 endoproteolysis on the urate crystal surface) in monocytes, and GM-CSF and TLR2 and TLR4 ligands in macrophages in vitro, to increase the capacity to phagocytose particulates, activate the NADPH oxidase, and cleave pro-caspase-1. Together, these heterogeneous priming signals transduce robust activation of the NLRP3 inflammasome complex in response to the illustrated second signals provided via urate crystal ingestion in mononuclear phagocytes.
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Comment on

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