Summary: Researchers have identified a mechanism by which fasting reduces inflammation: fasting raises blood levels of arachidonic acid, which suppresses the NLRP3 inflammasome and lowers inflammatory signaling. This finding helps explain some benefits of calorie restriction and suggests links between diet, common anti-inflammatory drugs, and protection from chronic diseases driven by inflammation.
A new study from the University of Cambridge, published in Cell Reports under the title “Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting,” reports that short-term fasting increases plasma arachidonic acid (AA). The elevated AA reduces activity of the NLRP3 inflammasome—a central cellular complex that drives inflammation—providing a plausible biochemical route for fasting’s anti-inflammatory effects.
The researchers also note that this mechanism may shed light on how some non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, produce anti-inflammatory effects. By blocking enzymes that normally break down AA, these drugs may raise AA levels transiently and thereby dampen inflammasome-driven inflammation.
Chronic inflammation is a known contributor to metabolic and age-related conditions such as obesity, type 2 diabetes, atherosclerosis, and neurodegenerative diseases like Alzheimer’s and Parkinson’s. While the inflammasome normally helps the body respond to infection and cell damage, excessive or misdirected inflammasome activity can promote harmful, persistent inflammation. The NLRP3 inflammasome in particular has been implicated in many of these conditions.
To explore how fasting alters inflammatory signaling, the team led by Professor Clare Bryant analyzed blood from 21 volunteers who consumed a small meal (500 kcal), fasted for 24 hours, and then ate a second 500-kcal meal. Lipid profiling revealed that AA levels rose during the fasting period and fell again after refeeding. In parallel lab experiments, adding AA to cultured human and mouse immune cells reduced NLRP3 inflammasome activity and lowered production of inflammatory cytokines such as IL-1β.
These results were surprising because AA has often been associated with pro-inflammatory pathways. However, the study shows that exogenous AA can act directly on immune cells to inhibit key signaling steps that activate NLRP3. Mechanistically, the researchers found that AA suppresses phospholipase C activity, which leads to reduced stimulation of the JNK pathway and ultimately lowers NLRP3 activation. The data support the view that AA can be a physiological regulator of inflammasome activity under certain metabolic conditions.
The work helps reconcile how dietary patterns and medications influence inflammation. A sustained high-calorie, high-fat Western diet has been linked to increased inflammasome activity, while calorie restriction and periodic fasting appear to reduce it. By showing that fasting transiently increases AA and that AA inhibits NLRP3, the study identifies one molecular route by which dietary intake influences systemic inflammation.
The findings also offer a potential explanation for an unexpected anti-inflammatory action of some NSAIDs. Because drugs like aspirin inhibit cyclooxygenase enzymes that normally metabolize AA, aspirin can temporarily elevate AA levels. This increase in AA could contribute to reduced NLRP3 activity and lower production of inflammatory cytokines. The authors caution, however, that taking aspirin for long-term disease prevention is not advised without medical supervision, given known risks such as gastrointestinal bleeding.
Professor Clare Bryant commented that while the AA effect appears short-lived after each fasting period, repeated or regular fasting practices might cumulatively reduce chronic inflammasome-driven inflammation associated with many modern diseases. The research strengthens the evidence base for the health benefits of calorie restriction and points to specific biochemical targets that could be explored for therapeutic modulation of inflammation.
Key Facts
- Fasting raises plasma arachidonic acid, which reduces NLRP3 inflammasome activity and inflammation.
- The mechanism helps explain how calorie restriction and intermittent fasting can protect against diseases linked to chronic inflammation.
- The findings suggest a reason why some NSAIDs that alter arachidonic acid metabolism may also reduce inflammasome-driven inflammation.
About this research
Author: Clare Bryant
Source: University of Cambridge
Contact: Clare Bryant, University of Cambridge
Image credit: Neuroscience News
Original Research: Open access. “Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting” by Milton Pereira et al., Cell Reports.
Abstract
Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting
Highlights
- Fasting reduces plasma IL-1β and increases arachidonic acid (AA) compared to the fed state.
- Exogenous AA suppresses NLRP3 inflammasome activity in human and mouse macrophages.
- AA inhibits phospholipase C, reduces JNK activation, and thereby lowers NLRP3 activity.
Summary
Elevated IL-1β, increased NLRP3 inflammasome activity, and systemic inflammation characterize chronic metabolic inflammatory syndromes, but the underlying mechanisms have been unclear. This study shows that fasting lowers plasma IL-1β while elevating AA. Lipid profiling of NLRP3-stimulated mouse macrophages revealed enhanced AA production and an NLRP3-dependent eicosanoid signature. Cyclooxygenase inhibition by NSAIDs reduced eicosanoid production but did not lower AA; nonetheless, NSAID treatment decreased IL-1β and IL-18 output following NLRP3 activation. Mechanistically, AA inhibits phospholipase C, reduces JNK1 stimulation, and thereby decreases NLRP3 activation. These data identify AA as an important physiological regulator of the NLRP3 inflammasome, explain why fasting reduces systemic inflammation, and suggest a molecular basis for some anti-inflammatory effects of NSAIDs.