Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism.
The inflammasomes are intracellular complexes that have an important role in cytosolic innate immune sensing and pathogen defense. Inflammasome sensors detect a diversity of intracellular microbial ligands and endogenous danger signals and activate caspase-1, thus initiating maturation and release of the proinflammatory cytokines interleukin-1β and interleukin-18. These events, although crucial to the innate immune response, have also been linked to the pathology of several inflammatory and autoimmune disorders. The natural isothiocyanate sulforaphane, present in broccoli sprouts and available as a dietary supplement, has gained attention for its antioxidant, anti-inflammatory, and chemopreventive properties. We discovered that sulforaphane inhibits caspase-1 autoproteolytic activation and interleukin-1β maturation and secretion downstream of the nucleotide-binding oligomerization domain-like receptor leucine-rich repeat proteins NLRP1 and NLRP3, NLR family apoptosis inhibitory protein 5/NLR family caspase-1 recruitment domain-containing protein 4 (NAIP5/NLRC4), and absent in melanoma 2 (AIM2) inflammasome receptors. Sulforaphane does not inhibit the inflammasome by direct modification of active caspase-1 and its mechanism is not dependent on protein degradation by the proteasome or de novo protein synthesis. Furthermore, sulforaphane-mediated inhibition of the inflammasomes is independent of the transcription factor nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and the antioxidant response-element pathway, to which many of the antioxidant and anti-inflammatory effects of sulforaphane have been attributed. Sulforaphane was also found to inhibit cell recruitment to the peritoneum and interleukin-1β secretion in an in vivo peritonitis model of acute gout and to reverse NLRP1-mediated murine resistance to Bacillus anthracis spore infection. These findings demonstrate that sulforaphane inhibits the inflammasomes through a novel mechanism and contributes to our understanding of the beneficial effects of sulforaphane.
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda, MD, USA.
Allison J
AJ
Greaney
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda, MD, USA.
Nolan K
NK
Maier
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda, MD, USA.
Stephen H
SH
Leppla
Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda, MD, USA mmoayeri@niaid.nih.gov.
Mahtab
M
Moayeri
D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010447:Peptide Hydrolases / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D000069292:Pyroptosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013454:Sulfoxides
D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D013454:Sulfoxides; D010447:Peptide Hydrolases; D020170:Caspase 1; D046988:Proteasome Endopeptidase Complex; C016766:sulforaphane
IL-1; NLRP1; NLRP3; caspase-1; inflammation