Research uncovers new mechanism controlling inflammation in immune cells

The study, published in Nature Metabolism, shows that inducible nitric oxide synthase (iNOS) can regulate levels of the inflammatory molecule itaconate without producing nitric oxide (NO) - challenging long-held assumptions about how this enzyme works.

Instead, the researchers found that iNOS directly binds to IRG1, the enzyme responsible for producing itaconate. This interaction reduces IRG1 activity and limits itaconate production, acting as a brake on inflammatory responses.

A potential new therapeutic target

This finding matters because it identifies a more precise way inflammation may be controlled. Rather than targeting nitric oxide signalling, which has broad effects across the body, future approaches could focus on disrupting or enhancing the interaction between iNOS and IRG1. This could open up new strategies for treating inflammatory conditions, including cardiovascular and metabolic diseases.

The team combined biochemical experiments, computational modelling and studies in both mouse and human cells to confirm the mechanism. They showed that cells lacking iNOS produced up to 15 times more itaconate during inflammation, while introducing iNOS suppressed itaconate levels - even when nitric oxide production was unchanged.

Marina Diotallevi, postdoctoral researcher in the Radcliffe Department of Medicine and lead author of the study, said: 'We were surprised to find that iNOS can regulate inflammation independently of nitric oxide. This changes how we think about its role in immune cells and highlights a completely new layer of metabolic control during inflammation.

'Further analysis demonstrated that iNOS and IRG1 form a stable complex positioning iNOS as part of a broader signalling hub linking metabolism and immune function.'

The findings suggest that iNOS has a wider role in immune regulation than previously recognised. By uncovering this nitric oxide–independent pathway, the study provides a clearer picture of how inflammatory responses are fine-tuned, and highlights a potential new target for therapeutic intervention.