Hamilton, Claire;
Olona, Antoni;
Leishman, Stuart;
MacDonald-Ramsahai, Kelly;
Cockcroft, Shamshad;
Larrouy-Maumus, Gerald;
Anand, Paras K;
(2022)
NLRP3 Inflammasome Priming and Activation Are Regulated by a Phosphatidylinositol-Dependent Mechanism.
ImmunoHorizons
, 6
(8)
pp. 642-659.
10.4049/immunohorizons.2200058.
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Abstract
Imbalance in lipid homeostasis is associated with discrepancies in immune signaling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signaling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. In this study, by using a mass spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ATP Binding Cassette Subfamily B Member 1 (ABCB1), which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically, Abcb1 deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI acyl lipids. Consequently, Abcb1 deficiency initiated the rapid degradation of Toll/IL-1R domain-containing adaptor protein, the TLR adaptor protein that binds PI (4,5)-bisphosphate, resulting in defective TLR-dependent signaling, and thus NLRP3 expression. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser291 position and contributed to blunted inflammasome activation. Exogenously supplementing wild-type cells with linoleic acid (LA), but not arachidonic acid, reconfigured PI acyl chains. Accordingly, LA supplementation increased Toll/IL-1R domain-containing adaptor protein degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on PGE2-induced protein kinase A signaling because pharmacological inhibition of this pathway in LA-enriched cells dephosphorylated NLRP3. Altogether, our study reveals, to our knowledge, a novel metabolic-inflammatory circuit that contributes to calibrating immune responses.
| Type: | Article |
|---|---|
| Title: | NLRP3 Inflammasome Priming and Activation Are Regulated by a Phosphatidylinositol-Dependent Mechanism |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.4049/immunohorizons.2200058 |
| Publisher version: | https://doi.org/10.4049/immunohorizons.2200058 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license. |
| Keywords: | Adaptor Proteins, Signal Transducing, Animals, Inflammasomes, Macrophages, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphatidylinositols, Signal Transduction |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10155236 |
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