Arachidonic Acid and Nitroarachidonic: Effects on NADPH Oxidase Activity

Arachidonic acid (AA) is a polyunsaturated fatty acid that participates in the inflammatory response mainly through bioactive-lipids formation in macrophages and also in the phagocytic NADPH oxidase 2 (NOX2) activation. NOX2 is the enzyme responsible for a huge superoxide formation in macrophages, essential to eliminate pathogens inside the phagosome. The oxidase is an enzymatic complex comprised of a membrane-bound flavocytochrome b ₅₅₈ (gp91^phox/p22^phox), three cytosolic subunits (p47^phox, p40^phox and p67^phox) and a Rac-GTPase. The enzyme becomes active when macrophages are exposed to appropriate stimuli that trigger the phosphorylation of cytosolic subunits and its migration to plasmatic membrane to form the active complex. It is proposed that AA stimulates NOX2 activity through AA interaction with different components of the NADPH oxidase complex. In inflammatory conditions, there is an increase in reactive oxygen and nitrogen species that results in the production of nitrated derivatives of AA, such as nitroarachidonic acid (NO₂-AA). NO₂-AA is capable to inhibit NOX2 activity by interfering with p47^phox migration to the membrane without affecting phosphorylation of cytosolic proteins. Also, NO₂-AA is capable to interact with protein disulfide isomerase (PDI), which is involved on NOX2 active complex formation. It has been demonstrated that NO₂-AA forms a covalent adduct with PDI that could prevent the interaction with NOX2 and it would explain the inhibitory effects of the fatty acid upon NOX2. Together, current data indicate that AA is an important activator of NOX2 formed in the early events of the inflammatory response, leading to a massive production of oxidants that may, in turn, promote NO₂-AA formation and shutting down the oxidative burst. Hence, AA and its derivatives could have antagonistic roles on NOX2 activity regulation.