Saturday, February 21, 2015

Fasting-induced ketone metabolite, β-hydroxybutyrate suppresses NALP3-mediated inflammasome activity

Inflammasome super-complex represents an ancient innate detection and defense mechanism against exogenous as well as endogenous irritants and toxins. Spontaneous inflammasome activity causes several known human immune-pathologies, like Muckle-Well and familial cold auto-inflammatory syndromes.  

New paper from Nature Medicine provided evidence showing that alternative energy source, β-hydroxybutyrate, elevated during fasting, calorie-restiction or high-intensity exercise, suppresses NALP3-mediated inflammasome activity.

Initially, the authors led by Prof. Vishwa Deep Dixit at the Yale School of Medicine, showed that β-hydroxybutyrate, but not another ketone body acetoacetate or short-chain fatty acids, butyrate or acetate, could inhibit NALP3-mediated inflammasome activity (AIM2- or NLRC4-mediated inflammasome activities were unaffected).

Suppression of NALP3-mediated inflammasome activity by β-hydroxybutyrate was independent of autophagy and required neither G protein-coupled receptor GPR109a signaling via β-hydroxybutyrate nor histone deacetylase inhibition by β-hydroxybutyrate.

The authors found that β-hydroxybutyrate suppressed NALP3-mediated inflammasome activity through its inhibition (by unknown mechanism) of potassium, K+ cation efflux from cytoplasm.

Finally, using cre-mediated mouse conditional models of human Muckle-Well and familial cold auto-inflammatory syndromes, the authors showed that stabilized form of β-hydroxybutyrate could suppress spontaneous NALP3-mediated inflammasome activity and ASC oligomerization characteristics to these gain-of-function NALP3 mutations.

In summary, these results indicate complex interplay between energy metabolism and inflammation. In condition of glucose deficiency, elevated level of β-hydroxybutyrate acts as a new source of ATP in brain and heart and at the same time inhibits NALP3-mediated inflammasome activity.

Leave your comments below and let me know what do you think about this paper.

David Usharauli

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