Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate

Ferreira, Ana M., Ferrari, Mariana I., Trostchansky, Andrés, Batthyany, Carlos, Souza, José M., Alvarez, María N., López, Gloria V., Baker, Paul R. S., Schopfer, Francisco J., O'Donnell, Valerie Bridget ORCID: https://orcid.org/0000-0003-4089-8460, Freeman, Bruce A. and Rubbo, Homero 2009. Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate. Biochemical Journal 417 (1) , pp. 223-234. 10.1042/BJ20080701

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Abstract

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARγ (peroxisome-proliferator-activated receptor γ) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase ∼20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-γ; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the •NO (nitric oxide) inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARγ and •NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-κB (nuclear factor κB) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	cholesteryl-nitrolinoleate; haem oxygenase-1; inducible nitric oxide synthase; inflammation; lipid nitration; macrophage.
Publisher:	Biochemical Society
ISSN:	0264-6021
Last Modified:	19 Oct 2022 10:39
URI:	https://orca.cardiff.ac.uk/id/eprint/25129

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