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Inflammasome: Starving Inflammation

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Inflammasome: Starving Inflammation RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 6 March 2015; doi:10.1038/nri3832 found that β-hydroxybutyrate INFLAMMASOME inhibited ASC oligomerization and speck formation. Both research groups also investigated the effect Starving inflammation of these inhibitors on K+ efflux, which triggers NLRP3 inflamma- Inflammasomes have an important treated with MCC950 followed by some activation. Coll et al. found no role in innate immunity, but their stimulation with the NLRP3 activator effect of MCC950 on intracellular aberrant activation is linked to chronic a low- ATP. In response to MCC950 treat- K+ levels, whereas Youm et al. found inflammatory diseases. Reporting carbohydrate ment, the levels of both IL‑1β and a that β-hydroxybutyrate prevented + in Nature Medicine, Coll et al. and ketogenic caspase 1 autocatalytic cleavage frag- K efflux in BMDMs in response to Youm et al. describe two compounds ment decreased in a dose-dependent differ­ent NLRP3 activators. — MCC950 and β-hydroxybutyrate, diet … could manner. Moreover, the authors Finally, both MCC950 and respectively — that specifically inhibit reduce the showed that MCC950 interferes with β-hydroxybutyrate were shown to have the NLRP3 (NOD-, LRR- and pyrin severity of the formation of NLRP3‑dependent inhibitory effects in mouse models of domain-containing 3) inflamma- ASC oligomers (‘specks’), which is a the human Muckle–Wells syndrome, some and have anti-inflammatory NLRP3‑ key event in inflammasome activa- which is associated with a mutation effects in mouse models of different mediated tion. However, MCC950 did not in NLRP3.Interestingly, MCC950 NLRP3‑dependent diseases. diseases prevent NLRP3 oligomerization or was also shown to have an inhibitory Activation of the NLRP3 NLRP3–ASC interactions. effect in peripheral blood mono- inflamma­some leads to activation Youm et al. searched for endog- nuclear cells from individuals with of caspase 1 and the release of enous mechanisms that could control Muckle–Wells syndrome. Youm et al. the pro-inflammatory cytokines NLRP3 deactivation. Ketone body found that feeding mice a ketogenic interleukin‑1β (IL‑1β) and IL‑18. β-hydroxybutyrate is produced in the diet increased β-hydroxybutyrate NLRP3‑mediated diseases are mainly liver and functions as an alternative levels in vivo, and that mice with a treated with compounds that target energy source during fasting, low- missense Nlrp3 mutation that leads IL‑1, and Coll et al. investigated carbohydrate diets and high-intensity to familial cold autoinflammatory whether the IL‑1β processing exercise, and as these states are syndrome — which is associated inhibitor MCC950 acts by inhibiting associated with altered immune cell with neutrophilia — were protected the inflammasome. Human and function, the authors investigated from neutrophilia when fed a ketogenic mouse macrophages were primed whether β-hydroxybutyrate could diet compared with chow-fed mice. with lipopolysaccharide (LPS) and act as an immune effector. Indeed, In conclusion, both MCC950 β-hydroxybutyrate inhibited both and β-hydroxybutyrate specifically ATP-induced cleavage of caspase 1 inhibit the NLRP3 inflammasome and the processing of the active form and could be promising treatments of IL‑1β in mouse bone marrow- for a variety of NLRP3‑mediated derived macrophages (BMDMs). inflammatory disorders. Furthermore, Additional experiments suggested that the study by Youm et al. indicates that β-hydroxybutyrate specifically acts a low-carbohydrate ketogenic diet — on a central signalling pathway that is which leads to increased levels of specific to the NLRP3 inflammasome. β-hydroxybutyrate — could reduce the Prolonged fasting is associated with severity of NLRP3‑mediated diseases. increased levels of β-hydroxybutyrate Elisabeth Kugelberg and reduced oxidative stress, which ORIGINAL RESEARCH PAPERS Coll, R. C. et al. could regulate inflammasome activa- A small-molecule inhibitor of the NLRP3 tion. However, the inhibitory effects inflammasome for the treatment of inflammatory of β-hydroxybutyrate on NLRP3 diseases. Nature Med. http://dx.doi.org/10.1038/ nm.3806 (2015) | Youm, Y.-H. et al. The ketone were not dependent on starvation-­ metabolite β-hydroxybutyrate blocks NLRP3 regulated mechanisms such as the inflammasome-mediated inflammatory disease. Nature Med. http://dx.doi.org/10.1038/nm.3804 production of reactive oxygen (2015) species and glyco­lytic inhibition. FURTHER READING Latz, E., Xiao, T. S. & Stutz, A. Instead, similar to the mechanism Activation and regulation of the inflammasomes. S. Bradbrook/NPG Nature Rev. Immunol. 13, 397–411 (2013) of action of MCC950, Youm et al. NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | APRIL 2015 © 2015 Macmillan Publishers Limited. All rights reserved.
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