Investigators Find Piezo1 Has Potential for the Future of Asthma Treatment

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Piezo1 is a protein produced by type 2 innate lymphoid cells when activated by an allergen and can limit the immune cell’s activity when triggered by a reaction.

Authors of a study published in the Journal of Experimenting Medicine found a protein that prevents a certain type of immune cell in the lung from becoming hyperactivated by allergens. The protein, Piezo1, could have significant implications for new therapeutic approaches in treating allergic asthma and other inflammatory lung conditions.1

Image credit: Goffkein | stock.adobe.com

Image credit: Goffkein | stock.adobe.com

The researchers knew that type 2 innate lymphoid cells (ILC2s)—a type of immune cells that reside in the lungs, skin, and other tissues—become activated when there is an allergen present. The ILC2s trigger a proinflammatory signal that drive the recruitment of other immune cells in the lungs. If left untreated, this can result in excessive inflammation of the lungs and tightening of the airways, increasing the difficulty of breathing for patients with asthma.1

“Given the importance of ILC2s in allergic asthma, there is an urgent need to develop novel mechanism-based approaches to target these critical drivers of inflammation in the lungs,” said Omid Akbari, professor of immunology and medicine at the University of South Carolina’s Keck School of Medicine, in a press release.1

The findings demonstrated that when activated by an allergen, ILC2s produce Piezo1, which can limit their activity. Piezo1 forms channels in the outer membranes of cells that open in response to changes in the cell’s environment, which allows for calcium to enter the cell and change its activity.1

In addition, although naïve pulmonary ILC2s were found to express low levels of Piezo1, the levels were induced efficiently with the use of IL-33. Further, ILC2s that lacked Piezo1 were activated more, demonstrating an upregulated oxidative phosphorylation signature that is often associated with greater ex vivo oxygen consumption rates which were confirmed in mouse models. This, according to the investigators, results in more severe airway hyperreactivity (AHR) associated with an exacerbated inflammatory response. The models also demonstrated decreased airway inflammation when ILC2 activity decreased, resulting in an alleviation of symptoms in the mice exposed to allergens.1,2

Alternatively, the investigators also found that Piezo1 activation with selective agonist Yoda1, and in response to IL-33, ILC2 function both in vivo and ex vivo was reduced. This significantly limited the development of AHR and lung inflammation in models of ILC2-dependent airway inflammation. The investigators note that this observation can mean a significant role for Piezo1 channels in ILC2 metabolism, because the treatment with Yoda1 reduced ILC2 mitochondrial function and “rewired” the cell energy source.1,2

The investigators also note that the findings in ILC2s isolated from human peripheral blood mononuclear cells. Along with the other findings, the authors emphasize that this identified a potentially novel regulator of ILC2 function, therefore opening possibilities in the development of downstream mechanisms that can be pharmacologically manipulated in order to improve the available therapies for allergic asthma.2

“Remarkably, treatment of these humanized mice with Yoda1 reduced airway hyperreactivity and lung inflammation, suggesting that Yoda1 may be used as a therapeutic tool to modulate ILC2 function and alleviate the symptoms associated with ILC2-dependent airway inflammation in humans,” said Akbari in the press release. “Future studies are therefore warranted to delineate the role of Piezo1 channels in human patients with asthma and develop Piezo1-driven therapeutics for the treatment of allergic asthma pathogenesis.”1

References
1. Rockefeller University Press. Researchers identify new way to inhibit immune cells that drive allergic asthma. News release. March 26, 2024. Accessed April 4, 2024. https://www.eurekalert.org/news-releases/1038220
2. Hurrell, B, Shen, S, Li, X, et al. Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity. J Exp Med. 6 May 2024; 221 (5): e20231835. doi:10.1084/jem.20231835
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