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

Milton Pereira; Jonathan Liang; Joy Edwards-Hicks; Allison M Meadows; Christine Hinz; Sonia Liggi; Matthias Hepprich; Jonathan M Mudry; Kim Han; Julian L Griffin; Iain Fraser; Michael N Sack; Christoph Hess; Clare E Bryant

doi:10.1016/j.celrep.2024.113700

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

Cell Rep. 2024 Feb 27;43(2):113700. doi: 10.1016/j.celrep.2024.113700. Epub 2024 Jan 23.

Authors

Affiliations

¹ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
² Department of Veterinary Medicine, University of Cambridge, Cambridge, UK; Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
³ The Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, UK.
⁴ Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA; Department of Biochemistry, University of Cambridge, Cambridge, UK.
⁵ Department of Biochemistry, University of Cambridge, Cambridge, UK.
⁶ University Hospital Basel, Basel, Switzerland.
⁷ Cantonal Hospital of Freiburg, Freiburg, Switzerland.
⁸ Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA.
⁹ Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
¹⁰ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: ceb27@cam.ac.uk.

Abstract

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.

Keywords: CP: Immunology; CP: Metabolism; NLRP3; eicosanoids; inflammasome; inflammation; lipidomics; metaflammation; prostaglandins.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Arachidonic Acid / therapeutic use
Eicosanoids
Fasting
Humans
Inflammasomes* / metabolism
Inflammation / metabolism
Interleukin-1beta / metabolism
Mice
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Arachidonic Acid
Interleukin-1beta
Anti-Inflammatory Agents, Non-Steroidal
Eicosanoids

Abstract

MeSH terms

Substances

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