Q&A: Limiting iron in immune cells may improve asthma symptoms

Key takeaways:

• Group 2 innate lymphoid cells (ILC2s) need iron to release cytokines once activated.
• ILC2s that do not have enough iron induce less airway inflammation and other symptoms of asthma.

When group 2 innate lymphoid cells become overactive, they can cause excessive inflammation and tighten the airways. But these immune cells depend on iron to generate energy.

Researchers of the Keck School of Medicine of USC have found that preventing iron uptake in these cells reduces the severity of asthma symptoms in mouse models. Also, researchers found a correlation between increased cellular iron uptake and asthma severity in patients with asthma.

These mechanisms indicate the potential for asthma therapies that operate by managing iron uptake, addressing the underlying cause of the disease.

Healio spoke with Benjamin P. Hurrell, PhD, assistant professor, department of molecular microbiology and immunology, Keck School of Medicine, to find out more.

Healio: Could you summarize the role of group 2 innate lymphoid cells (ILC2) in asthma activity?

Hurrell: They are a type of immune cell that play a significant role in asthma due to their location in barrier tissues such as the lungs. When allergens enter the airways, they can rapidly activate ILC2s and lead to asthma symptoms. Once activated, ILC2s release cytokines (the messengers of the immune system) such as IL-5 and IL-13, which promote eosinophil recruitment, mucus production, inflammation and airway constriction, all of which are hallmarks of asthma. Our research, along with that of others, shows that reducing the activation of ILC2s independently of other cells can alleviate asthma-related symptoms in mice.

Healio: What impact does iron have on ILC2 cells?

Hurrell: We found that iron has a significant impact on ILC2s. Simply, ILC2s cannot function properly without enough iron. ILC2s, like many other immune cells, have high metabolic demands to support their rapid proliferation and cytokine production during immune responses. We found that iron and ILC2 metabolism are intricately linked. Without iron, ILC2s fail to generate enough energy to proliferate and produce their effector cytokines. Consequently, they induce less lung inflammation and cardinal features of asthma such as airway constriction. Maintaining iron homeostasis is therefore crucial for proper ILC2 function and immune regulation.

Healio: How did you and your team limit this impact that iron has on ILC2 cells?

Hurrell: This is a very important point. A strength of our study is that we limited cellular iron in ILC2s with three different approaches.

We first blocked iron uptake by ILC2s using an anti-transferrin receptor 1 (TfR1) antibody. In the blood, iron binds to a protein called transferrin and enters cells by binding TfR1 on the surface of cells. By blocking the receptor of transferrin using an antibody, ILC2s could not uptake the iron they needed, and this affected their activation. This strategy is successfully used in some cancer treatments, as cancer cells need a lot of iron.

The second approach was to block cellular iron usage in ILC2s. We achieved this by using an iron chelator called deferiprone (Ferriprox, Chiesi Farmaceutici), which binds to iron in ILC2s and prevents it from being used. Iron chelators are traditionally used to treat patients with iron overload with great success.

The last approach was to physiologically lower iron levels in mice by using a protein called a mini-hepcidin. Hepcidin is the physiological hormone produced by our body to reduce our iron levels when we need it. By introducing a synthetic hepcidin (called mini-hepcidin) in mice, we lowered systemic iron and by consequence iron uptake by ILC2s during inflammation.

Healio: Could you describe the impact that this process had on asthma when you tested it in human patients?

Hurrell: Another strength of our study is that we analyzed the data obtained from patients with different severities of asthma. The samples came from an established cohort of patients at USC, requiring the collaboration from both clinical and research teams. What we found is that patients with a higher severity of asthma expressed more TfR1 on their ILC2s compared with patients with less severe asthma. The higher expression of TfR1 was linked to a higher uptake of iron, and these ILC2s were also much more activated, which replicated our findings obtained in mice. When we limited iron availability in human ILC2s in culture, this also decreased their activation, suggesting that these treatments could potentially reduce ILC2 activation in patients with asthma.

Healio: How could this be used as a potential therapy for patients with asthma?

Hurrell: It is important to note that iron is also needed for other aspects of our body such as oxygen transport to tissues, so we need to take this into account. One thing that we did not do in our study is to find a restricted way to target ILC2s in the lungs and reduce iron uptake locally without impacting other systems in the body. This is what we are currently working on.

Healio: What advantages would therapies that target iron have over other asthma therapies?

Hurrell: The current standard of care for allergic asthma involves the use of bronchodilators and immunosuppressive drugs, often administered indefinitely with varying side effects. Steroid inhalers and pills can control symptoms to keep patients alive, but they are not attacking the underlying pathophysiology of the disease. We hope that by targeting the cause of the disease rather than treating the consequences, we can ultimately offer better solutions for patients.

References:

• Hurrell BP, et al. Sci Transl Med. 2024;doi:10.1126/scitranslmed.adk4728.
• USC study reveals role of iron in allergic asthma and points to potential new therapies. https://keck.usc.edu/news/usc-study-reveals-role-of-iron-in-allergic-asthma-and-points-to-potential-new-therapies/. Published May 8, 2024. Accessed June 3, 2024.

For more information:

Benjamin P. Hurrell, PhD, can be reached at hurrell@usc.edu.