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
Affiliations
Milton Pereira
Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
Jonathan Liang
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
Joy Edwards-Hicks
The Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, UK
Allison M. Meadows
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
Christine Hinz
Department of Biochemistry, University of Cambridge, Cambridge, UK
Sonia Liggi
Department of Biochemistry, University of Cambridge, Cambridge, UK
Matthias Hepprich
University Hospital Basel, Basel, Switzerland
Jonathan M. Mudry
Cantonal Hospital of Freiburg, Freiburg, Switzerland
Kim Han
Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA
Julian L. Griffin
Department of Biochemistry, University of Cambridge, Cambridge, UK
Iain Fraser
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
Michael N. Sack
Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA
Christoph Hess
The Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, UK
Clare E. Bryant
Department of Veterinary Medicine, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK; Corresponding author
Summary: 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.
