A Mechanism by Which Fasting Suppresses Inflammation via the Inflammasome

Some of the benefits of fasting in later life derive from suppression of the chronic, unresolved inflammatory signaling characteristic of old age. As is usually the case in such matters, how much of the overall beneficial effect of fasting on long-term health, mortality, and life expectancy is due to this mechanism remains an open question. Similarly, while researchers here focus on one specific way in which inflammation is suppressed following fasting, via an interaction with the inflammasome, whether this specific interaction is a large or a small contribution to the whole remains to be determined, even given the interesting comparison with nonsteroidal anti-inflammatory drugs.

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.

Link: https://doi.org/10.1016/j.celrep.2024.113700

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