Immune cells encounter complex mechanical cues and convert mechanical changes to electrochemical signals through mechanosensitive ion channels (MSCs). These channels sense force and pressure in immune cells, driving the inflammatory response in highly mechanical organs. Researchers at the Keck School of Medicine, University of Southern California, have discovered a promising new approach to treating allergic asthma. Their innovative study, published in the Journal of Experimental Medicine (JEM), highlights the crucial role of a protein called Piezo1 in regulating the immune response in the lungs.
Type 2 innate lymphoid cells (ILC2s), found in lung tissues, play a key role in immune response in allergic asthma. Upon encountering allergens, ILC2s become hyperactivated, releasing proinflammatory signals that exacerbate inflammation and airway constriction. Dr.Hurrell and colleagues emphasize the critical need for innovative treatments targeting ILC2s. The researchers made a breakthrough discovery regarding the role of Piezo1 in regulating ILC2 activity. When exposed to allergens, ILC2s produce Piezo1, a protein that serves as a regulator by limiting their hyperactivity. Piezo1 forms channels in cell membranes, responding to mechanical changes in the cell’s environment and modulating calcium influx, thereby influencing cellular activity.
In their experiments, the absence of Piezo1 led to increased activity in mouse ILC2s exposed to allergenic signals, resulting in increased airway inflammation. Conversely, treatment with Yoda1, a drug that activates Piezo1 channels, effectively reduced ILC2 activity, mitigated airway inflammation, and relieved symptoms in allergen-exposed mice. Furthermore, the researchers observed significant metabolic changes in ILC2s upon Piezo1 activation. Treatment with Yoda1 not only reduced ILC2 activity but also impacted mitochondrial function and altered cellular energy sources, underscoring the multifaceted role of Piezo1 in regulating the immune response.
The researchers found that human ILC2s also produce Piezo1, suggesting potential applicability in human asthma cases. Testing Yoda1 on mice with humanized ILC2s yielded promising results, with reduced airway hyperreactivity and lung inflammation. These findings highlight the translational potential of Piezo1-targeted therapies in treating allergic asthma in humans. Hurell et.al underscore the importance of further investigation into Piezo1 channels’ role in human asthma patients and 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.
The discovery of Piezo1’s regulatory role in ILC2 activity presents a promising therapeutic target for allergic asthma. By modulating immune response in the lungs, Piezo1 activation offers a novel approach to alleviate inflammation and improve respiratory function in asthma patients. Further research in this area holds immense potential for the development of effective treatments addressing the underlying mechanisms of allergic asthma.
Reference
Hurrell BP, Shen S, Li X, Sakano Y, Kazemi MH, Quach C, et al. Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity. Journal of Experimental Medicine. 2024 Mar 26;221(5):e20231835.