Gatekeeping protein could be key target for controlling severe asthma

New study highlights how ABIN-2’s role in regulating allergic airway inflammation could make it a potential target for treating asthma.

In the study, published yesterday in the Journal of Experimental Medicine, scientists generated a genetically modified mouse strain with a defective ABIN-2 protein and investigated how this alteration affected the development of airway inflammation induced by house dust mites. This builds on previous work which suggested that the enzyme TPL-2, which binds to ABIN-2, plays an important role in keeping airway inflammation in check. However, the latest study – conducted as part of a research collaboration between Imperial College London, the Francis Crick Institute and Genentech – identified a key role for ABIN-2 in regulating airway inflammation, while showing that TPL-2 enzymatic activity is not required.

Asthma is one of the world’s most significant non-communicable diseases, and is the most common chronic disease among children. The disease is characterised by recurrent attacks of breathlessness and wheezing which are caused by tightened airways. WHO currently estimates that 235 million people suffer from asthma globally, and that asthma deaths will increase in the future if better ways of controlling and managing the disease cannot be found. The fundamental causes of asthma, however, are still not understood, which makes it difficult to develop new treatments.

Investigating immune response

The team, led by Imperial's Professor Steve Ley, set out to further investigate the role of TPL-2 in limiting the development of allergic airway inflammation. Building on their previous findings, the team developed a mutant mouse strain which expresses a signalling-deficient form of ABIN-2 – a scaffolding protein that binds to TPL-2.

In preventing ABIN-2 from performing its vital signalling function, the researchers noticed significant changes in lung dendritic cells, which typically work to capture allergens in the airways and activate the immune system. Dendritic cells with defective ABIN-2 signalling secreted more CCL24 – a kind of small signalling protein that promotes inflammation and mucus production. The mutant mice consequently developed more severe allergic airway inflammation.

Next steps

The team hope that their findings can provide a more detailed understanding of how dendritic cells regulate the development severe asthma.

Dr Mark Wilson of Genentech added: “Although these are very early days, our results suggest that it may be possible to prevent severe airway inflammation and asthma by manipulating ABIN-2 signalling in dendritic cells”.

On the broader significance of the study, Professor Ley commented: “Our study shows that inhibition of TPL-2 enzyme activity does not promote allergic airway inflammation. This is an important finding for the continued development of TPL-2 as an anti-inflammatory and cancer drug target, since it suggests that TPL-2 inhibitors would not exacerbate asthma.”

‘A20-binding inhibitor of NF-κB (ABIN) 2 negatively regulates allergic airway inflammation’ by Sonia Ventura, Florencia Cano, Yashaswini Kannan et al., is published in the Journal of Experimental Medicine.

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