Breakthrough Discovery Unveils iNOS's Hidden Role in Inflammation Control

Researchers at the University of Surrey and the University of Oxford have made a groundbreaking discovery that could transform how we approach treatments for inflammatory diseases. Their work reveals that the protein inducible nitric oxide synthase, commonly known as iNOS, plays a dual role in the immune system. Long recognized for producing nitric oxide to fuel inflammation during infections or injuries, iNOS also physically interacts with another protein called immune-responsive gene 1, or IRG1, to fine-tune the body's response.

This interaction occurs inside the mitochondria of immune cells, specifically macrophages, where iNOS binds directly to IRG1. By doing so, it prevents IRG1 from generating itaconate, a key metabolite that acts as a natural brake on excessive inflammation. This finding, detailed in a study published in Nature Metabolism on April 10, 2026, challenges decades-old assumptions and opens new avenues for precision therapies. Led by Dr. Mark Crabtree from Surrey's School of Biosciences and Medicine, the team used advanced techniques like co-immunoprecipitation, mass spectrometry, and computational modeling to confirm the binding's stability and specificity across mouse and human models.

The Burden of Inflammatory Diseases in Europe

Inflammatory diseases represent a major health challenge across Europe, affecting millions and straining healthcare systems. Rheumatoid arthritis alone impacts about 1% of the European population, leading to joint damage, chronic pain, and reduced quality of life. Inflammatory bowel diseases like Crohn's disease and ulcerative colitis affect around 0.5% of Europeans, with rising incidence rates particularly in northern countries. Cardiovascular conditions linked to chronic inflammation, such as atherosclerosis, contribute to over 4 million deaths annually in the EU.

Current treatments often rely on broad immunosuppressants like corticosteroids or biologics targeting specific cytokines, but these come with side effects including increased infection risk and incomplete efficacy. The Surrey-Oxford discovery highlights a need for more targeted interventions that modulate inflammation without broadly suppressing the immune system, potentially benefiting the 10-15% of Europeans living with chronic inflammatory conditions.

Decoding the iNOS-IRG1 Mechanism Step by Step

To grasp this discovery, consider the inflammatory cascade. When pathogens or damage signals activate immune cells, iNOS expression surges, traditionally viewed as pro-inflammatory due to nitric oxide (NO) production. However, the study shows an NO-independent pathway: iNOS, stabilized by its cofactor tetrahydrobiopterin (BH4), adopts a specific conformation that allows high-affinity binding to IRG1.

1. Activation Phase: Macrophages detect danger via Toll-like receptors, upregulating both iNOS and IRG1.
2. Mitochondrial Localization: Both proteins localize to mitochondria, where IRG1 converts cis-aconitate to itaconate.
3. Binding Event: iNOS forms a stable heterotetramer with IRG1 ((iNOS)₂-(IRG1)₂), with dissociation constant around 174 nM, sequestering IRG1.
4. Inhibition: Blocked IRG1 fails to produce itaconate (over 15-fold reduction observed), limiting anti-inflammatory effects and sustaining controlled inflammation.
5. Resolution: As signals wane, iNOS levels drop, freeing IRG1 to restore balance.

This physical interaction, validated by AlphaFold modeling and surface plasmon resonance, explains why iNOS knockout cells overproduce itaconate post-stimulation. For full details, see the original paper in Nature Metabolism.

Revolutionizing Rheumatoid Arthritis Therapies

Rheumatoid arthritis (RA), an autoimmune disorder causing synovial inflammation and joint erosion, exemplifies where this discovery shines. Europe's RA prevalence stands at 0.5-1%, with women three times more affected. Existing DMARDs (disease-modifying antirheumatic drugs) like methotrexate suppress broad inflammation but fail 30-40% of patients. Targeting the iNOS-IRG1 axis could selectively enhance itaconate's protective effects, reducing cytokine storms without global immunosuppression. Preclinical models suggest disrupting the bind could amplify itaconate's alkylation of KEAP1-NRF2 pathway, bolstering antioxidant defenses in synovial fibroblasts.

Hope for Inflammatory Bowel Disease Patients

Crohn's disease and ulcerative colitis disrupt gut homeostasis, with Europe reporting 2.5-3 million cases. Symptoms like abdominal pain and diarrhea stem from dysregulated macrophage responses. The Surrey-Oxford finding implicates iNOS-IRG1 in intestinal inflammation: in IBD models, elevated iNOS correlates with muted itaconate, exacerbating tissue damage. Therapeutic strategies might involve small molecules mimicking BH4 disruption, restoring itaconate to inhibit NLRP3 inflammasome activation. Early trials could leverage BH4 analogs already in cardiovascular use, accelerating translation.

More on the university collaboration via Surrey's announcement.

Cardiovascular Disease: A New Frontier

Chronic inflammation drives atherosclerosis, Europe's leading killer with 45% of deaths. iNOS in vascular endothelium promotes plaque instability via NO, but the IRG1 link suggests metabolic reprogramming. In endothelial cells, iNOS binding limits itaconate-mediated glycolysis shifts, sustaining pro-inflammatory states. Disrupting this could stabilize plaques, complementing statins. Funded by the British Heart Foundation, this work underscores UK higher education's role in cardiovascular research hubs.

UK Higher Education's Collaborative Powerhouse

The University of Surrey, renowned for biosciences and health innovation, and Oxford, a global leader in biomedical research, exemplify Europe's research ecosystem. Surrey's Cardiovascular Biochemistry group integrates structural biology with immunology, while Oxford's Target Discovery Institute provides mass spectrometry expertise. This partnership, involving techniques from AlphaFold to molecular dynamics, highlights interdisciplinary training vital for PhD students and postdocs. Such collaborations attract EU funding like Horizon Europe, fostering talent in protein science.

From Bench to Bedside: Path to New Drugs

Translating this into therapies requires screening inhibitors of the iNOS-IRG1 interface. Computational docking identifies BH4-binding pockets for small molecules. Preclinical validation in humanized mouse IBD models could precede Phase I trials. Challenges include specificity to avoid off-target NO effects, but the high-affinity site offers promise. Biotech spinouts from Surrey-Oxford could commercialize, mirroring successes like Oxford's COVID vaccine.

Career Opportunities in Europe's Biomedical Research

This discovery spotlights demand for experts in immunometabolism. UK universities like Surrey offer MSc/PhD programs in Biochemistry and Immunology, with research assistant roles abundant. Europe's ERC grants support early-career researchers, while industry partners seek protein engineers. For aspiring academics, publications in Nature Metabolism boost tenure tracks.

Europe's Leadership in Inflammatory Research

Building on EU initiatives like IMI-2, this work positions UK institutions post-Brexit as hubs. Collaborations with EMA expedite approvals, potentially fast-tracking iNOS modulators. Broader impacts include personalized medicine via BH4 genotyping, addressing Europe's aging population where inflammation rises 20% per decade post-50.

Related coverage in BBC News.

Photo by Annie Spratt on Unsplash

Future Outlook and Research Horizons

Next steps include CRISPR screens for interactome partners and human macrophage organoids. Long-term, integrating with AI-driven drug design could yield candidates by 2030. Surrey and Oxford's synergy promises sustained innovation, benefiting Europe's health landscape.