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@article{Hamilton:2022,
author = {Hamilton, C and Olona, A and Leishman, S and MacDonald-Ramsahai, K and Cockcroft, S and Larrouy-Maumus, G and Anand, P},
journal = {ImmunoHorizons},
title = {NLRP3 inflammasome priming and activation are regulated by a phosphatidylinositol-dependent mechanism},
url = {https://www.immunohorizons.org/content/6/8/642},
volume = {6},
year = {2022}
}

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TY - JOUR
AB - 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. Here, by employing a mass-spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NLRP3 inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter 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 TIRAP, the TLR adaptor protein which 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 WT cells with linoleic acid, but not arachidonic acid, reconfigured PI acyl chains. Accordingly, linoleic acid supplementation increased TIRAP degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on prostaglandin E2-induced protein kinase A signaling as pharmacological inhibition of this pathway in linoleic acid-enriched cells dephosphorylated NLRP3. Altogether, our study reveals a novel metabolic-inflammatory circuit which contributes to calibrating immune responses.
AU - Hamilton,C
AU - Olona,A
AU - Leishman,S
AU - MacDonald-Ramsahai,K
AU - Cockcroft,S
AU - Larrouy-Maumus,G
AU - Anand,P
PY - 2022///
SN - 2573-7732
TI - NLRP3 inflammasome priming and activation are regulated by a phosphatidylinositol-dependent mechanism
T2 - ImmunoHorizons
UR - https://www.immunohorizons.org/content/6/8/642
UR - http://hdl.handle.net/10044/1/98615
VL - 6
ER -

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