CCL2 nitration is a negative regulator of chemokine-mediated inflammation

Catriona E. Barker (1) , Sarah Thompson (1) , Graeme O’boyle , Hugues Lortat-Jacob (2) , Neil S. Sheerin (1) , Simi Ali (1) , John A. Kirby (1)

1 Newcastle University [Newcastle]
2 IBS - UMR 5075 - Institut de biologie structurale

Chemokines promote leukocyte recruitment during inflammation. The oxidative burst is an important effector mechanism, this leads to the generation of reactive nitrogen species (RNS), including peroxynitrite (ONOO). The current study was performed to determine the potential for nitration to alter the chemical and biological properties of the prototypical CC chemokine, CCL2. Immunofluorescence was performed to assess the presence of RNS in kidney biopsies. Co-localisation was observed between RNS-modified tyrosine residues and the chemokine CCL2 in diseased kidneys. Nitration reduced the potential of CCL2 to stimulate monocyte migration in diffusion gradient chemotaxis assays (p < 0.05). This was consistent with a trend towards reduced affinity of the nitrated chemokine for its cognate receptor CCR2b. The nitrated chemokine was unable to induce transendothelial monocyte migration in vitro and failed to promote leukocyte recruitment when added to murine air pouches (p < 0.05). This could potentially be attributed to reduced glycosaminoglycan binding ability, as surface plasmon resonance spectroscopy showed that nitration reduced heparan sulphate binding by CCL2. Importantly, intravenous administration of nitrated CCL2 also inhibited the normal recruitment of leukocytes to murine air pouches filled with unmodified CCL2. Together these data suggest that nitration of CCL2 during inflammation provides a mechanism to limit and resolve acute inflammation.

Mots clés: Chemokine; Inflamation; Heparan sulfate; Oxidative burst; Reactive nitrogen species; Nitration

Domaines: Biochimie, Biologie Moléculaire

Catriona E. Barker, Sarah Thompson, Graeme O’boyle, Hugues Lortat-Jacob, Neil S. Sheerin, et al.. CCL2 nitration is a negative regulator of chemokine-mediated inflammation. Scientific Reports, 2017, 7, pp.44384. ⟨10.1038/srep44384⟩. ⟨hal-01491109⟩