Fine-tuning inflammasome activity with a small molecule or ketogenic diet

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Science Translational Medicine  18 Mar 2015:
Vol. 7, Issue 279, pp. 279ec47
DOI: 10.1126/scitranslmed.aaa9862

Multiprotein inflammasome complexes are essential components of the innate immune system that usually help to ward off a variety of infections. Abberrent activation of one type of inflammasome, NLRP3, however, is associated with complex diseases such as diabetes, atherosclerosis, gout, and multiple sclerosis. Diverse stimuli—ATP, cholesterol crystals, fatty acids, amyloids and envionmental toxins—induce the inflammasome to trigger the sterile inflammation that underlies all of these multifactorial diseases. Two new studies have discovered molecular blockers of the NLRP3 inflammasome. Coll et al. report that MCC950, a small molecule identified more than a decade ago as an IL-1β–processing inhibitor, is a potent and specific inhibitor of the NLRP3 inflammasome in macrophages. Youm and colleagues describe an endogenous compound, a ketone known as B-hydroxybutyrate (BHB); when induced with prolonged fasting or intense exercise, it serves as an alternative ATP source and deactivates NLRP3.

BHB supplementation or a ketogenic diet suppressed NLRP3 action and ameliorated symptoms in mouse models of Muckle-Wells syndrome and familial cold autoinflammatory syndrome (a gain-of-function mutation of NLRP3 gene). MCC950 also reversibly inhibited IL-18 and ameliorated symptoms in Muckle-Wells syndrome mice, but not in mice bearing the NLRP1-activating mutation. Additionally, MCC950 alleviated the symptoms of experimental autoimmune encephalitis (EAE) that develops in an NLRP3-dependent manner in mice. MCC950 also blocked human NLRP3 in blood cells obtained from patients with Muckle-Wells syndrome.

Exactly how these agents block NLRP3 action is not yet clear. MCC950 did not alter ASC-NLRP3 association or K+ efflux from cells (upstream of NLRP3), whereas BHB prevented K+ efflux. The actual molecular target of MCC950 could be NLRP3 itself or a posttranslational modification that alters NLRP3’s activation.

Blocking NLRP3 represents a promising therapeutic approach to complex diseases. This avenue has advantages over current antibody-based agents that ablate secreted IL-1β and compromise immune defense against infections. MCC950 is worth testing in clinical trials, as are ketogenic diets or diets low in carbohydrates, for the treatment and prevention of complex metabolic and inflammatory diseases.

Y.-H. Youm et al., The ketone metabolite β-hyroxybutyrate blocks NLRP3 infalmmasome–mediated inflammatory disease. Nat. Med. 21, 10.1038/nm.3804 (2015).[Abstract]

R. C. Coll et al., A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).[Abstract]

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