Researchers at the Keck School of Medicine of the University of Southern California have discovered that a protein called Piezo1 prevents type 2 innate lymphoid cells (ILC2s) in the lung from becoming hyperactivated by allergens. The results of their studies, including tests in experimental mouse models of allergic asthma, and in humanized mice, identified for the first time a crucial role for Piezo1 channels on ILC2 function and the development of airway hyper-reactivity (AHR). The findings indicate that switching on Piezo1 could represent a new therapeutic approach to reducing lung inflammation and treating allergic asthma.

The team, headed by Omid Akbari, PhD, professor of medicine at the Keck School of Medicine, reported on the findings in the Journal of Experimental Medicine, in a paper titled “Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity,” in which they wrote, “Our studies define Piezo1 as a critical regulator of ILC2s, and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.”

ILC2s are a type of immune cell that resides in the lungs, skin, and other tissues of the body. “They are the dominant ILC population in the lungs at steady state and share features of both innate and adaptive immune cells.” Moreover, the team continued, “ILC2s are a dynamic population in the lungs, as we and others have previously shown that modulating their activation can have a direct impact on the pathology of lung inflammation.”

ILC2s in the lungs become activated in the presence of allergens and produce proinflammatory signals that drive the recruitment of other immune cells into the lungs. Unchecked, this can result in excessive inflammation and a tightening of the airways, making it difficult for asthma patients to properly breathe. “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,” Akbari said.

Akbari and colleagues discovered that, when they are activated by an allergen, ILC2s start to produce a protein called Piezo1 that can limit their activity. Piezo1 forms channels in the outer membranes of cells that open in response to mechanical changes in the cell’s environment, allowing calcium to enter the cell and change its activity. “The recent discovery of Piezo channels has gathered strong interest in the field of immunology,” the team pointed out. “Piezo1 channels are highly expressed in the lungs—in particular in endothelial and epithelial, smooth muscle cells, macrophages, and monocytes … Several studies highlight a crucial role for Piezo1 in both innate and adaptive immune cells.”

Akbari’s team found that, in the absence of Piezo1, mouse ILC2s became more active than normal in response to allergenic signals, and the animals developed increased airway inflammation. In summary, our ex vivo and in vivo findings combine to suggest that a lack of Piezo1 is associated with increased ILC2 function, in turn exacerbating the development of ILC2-dependent AHR and airway inflammation.”

In contrast, treatment with a drug called Yoda1 that switches on Piezo1 channels reduced the activity of ILC2s, decreased airway inflammation, and alleviated the symptoms of allergen-exposed mice. The group’s observations suggest a significant role for Piezo1 channels in ILC2 metabolism, as treatment with Yoda1 reduced ILC2 mitochondrial function and rewired the cells’ energy source. “Yoda1 is a selective Piezo1 agonist leading to downstream effects on gene transcription in a multitude of cells,” the scientists explained. “Together, our findings using Yoda1 ex vivo and in vivo suggest that Piezo1 activation limits ILC2 function.”

Finally, the researchers determined that human ILC2s (hILC2s) also produce Piezo1. “In confirmation of our murine studies, we report that Piezo1 activation in human ILC2s is able to reduce ILC2 activation and oxidative metabolism,” they wrote. They tested the effects of Yoda1 on mice whose ILC2s had been replaced with human immune cells.

Activation of ILC2s causes inflammation in mouse lungs (left), but this is reduced by treatment with Yoda1 to stimulate Piezo1 channels (right).
Activation of ILC2s causes inflammation in mouse lungs (left), but this is reduced by treatment with Yoda1 to stimulate Piezo1 channels (right). [©2024 Hurrell et al. Originally published in Journal of Experimental Medicine.]

“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,” Akbari says. “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.”

In their discussion, the authors wrote, “Our major finding is that activation of Piezo1 channels in ILC2s ameliorates the development of AHR and lung inflammation in murine models and humanized mice.” To their knowledge, they further stated, the study is the first report identifying a role for Piezo1 channels in ILC2s, particularly in the lungs. “Given the importance of ILC2s in allergic asthma and the need for novel mechanism-based approaches to target the main drivers of inflammation in particular in the lungs, we propose that Piezo1 activation could represent a novel mechanism-based approach for the treatment of ILC2-driven allergic asthma.”

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