Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting

Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work. [Display omitted] •In fasting compared to fed subjects, plasma IL-1β is lower and arachidonic acid (AA) is higher•Exogenous AA impairs NLRP3 inflammasome activity in human and mouse macrophages•AA inhibits phospholipase C and reduces JNK stimulation and hence NLRP3 activity By studying how arachidonic acid (AA) impacts the inflammasome, Pereira et al. demonstrate that AA inhibits NLRP3-mediated IL-1β production by blocking the activities of phospholipase C and the downstream protein kinases PKD and JNK. This provides a mechanistic basis for the inverse relationship between serum levels of AA and IL-1β.