In the lung disease COPD, recycling of a disease-promoting molecule is impaired by a specific ion channel. This potential treatment approach for COPD was discovered by an international research team that included scientists from the DZL and the German Consortium for Translational Cancer Research (DKTK).
DZL scientist Dr. Ali Önder Yildirim from Helmholtz Zentrum München demonstrated along with Prof. Christian Grimm and Prof. Martin Biel (both Ludwig-Maximilians-Universität Munich) that certain ion channels in immune cells are crucially involved in the inflammatory process of chronic obstructive pulmonary disease (COPD). Potentially, these ion channels could be a target for new therapies.
Alveolar macrophages are immune cells found on the surface of the alveoli. They release various messenger substances that promote inflammation. These include the so-called macrophage elastase MMP12. This molecule was already known to promote the development of emphysema when too much of it is present. As the scientists were now able to show in two independent mouse models, the ion channel TRPML3 plays an essential role in the regulation of MMP12: The channel is found in the lung almost exclusively in alveolar macrophages. If it is switched off, the corresponding knockout mice showed increased MMP12 levels in the lung and developed lung damage. When they were treated with tobacco smoke or elastase-both of which promote COPD-the damage worsened.
Inflammation impairs reuptake
Using a variety of methods, the researchers then examined the expression and function of TRPML3 in the lung to elucidate how MMP12 levels are regulated. "To our surprise, we found that in COPD, it is not the secretion of MMP12 that is impaired, but endocytosis. So inflammation does not cause more MMP12 to be secreted, but the reuptake of excess MMP12 by TRPML3 does not function sufficiently," Grimm says. "In consistence, by using patch clamp technology, we were able to demonstrate that the channel is expressed primarily in the so-called early endosomes, whose function is to take up particles."
Comparison of samples from human patients with and without COPD showed that TRPML3 is highly upregulated in COPD patients, meaning that it is produced at an increased level. The scientists assume that in this way the body tries to counteract harmful influences by breaking down as much of the harmful MMP12 as possible. Overall, these results thus suggested that TRPML3 is an important regulator of MMP-12 uptake by alveolar macrophages and could serve as a therapeutic target for COPD.
Original publication: Spix B, Butz ES, Chen CC, et al. Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nat Commun. 2022;13(1):318. published 2022 Jan 14. doi: 10.1038/s41467-021-27860-x
Source: LMU press release