Ion Channel in Immune Cells May Serve as Target for COPD Treatment

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Researchers have discovered that an ion channel protein called TRPML3 may be a new therapeutic target for chronic obstructive pulmonary disease (COPD).

Their preclinical study found that the protein regulates the levels of MMP-12, a molecule produced in lung immune cells and known to drive COPD. Mice lacking the protein exhibited COPD-like disease with increased levels of MMP-12 in the lung. However, treatment with a TRPML-activating molecule reduced MMP-12 levels in healthy mice.

These findings shed light on the molecular mechanisms behind the higher-than-normal levels of MMP-12 found in COPD patients.

The study, “Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice,” was published in the journal Nature Communications.

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COPD is characterized by excessive airway inflammation, and abnormal repair and remodeling of the lung tissue, often resulting in the progressive destruction of alveoli — the tiny lung air sacs responsible for gas exchange.

The disease is caused mainly by repeated lesions due to long-term exposure to irritants, such as cigarette smoke, air pollution, and chemical gases.

Previous studies showed that people with emphysema, a severe form of COPD, have excess levels of MMP-12, a molecule mostly secreted, or produced, by alveolar macrophages and known to mediate the development of lung damage and emphysema.

Alveolar macrophages are a type of immune cell that reside in the alveoli and act as the first line of defense in the lungs, “clearing the air spaces of infectious, toxic, or allergic particles,” the researchers wrote.

While MMP-12’s contribution to emphysema and COPD is well-established, little is known about the mechanisms that regulate its secretion and clearance in the alveoli.

Now, a team of researchers in Germany, along with colleagues in other countries, discovered that MMP-12 levels are regulated by a protein called TRPML3.

TRPML3, also known as mucolipin-3, is an ion channel mainly found at the membrane of cellular vesicles called endosomes and lysosomes. Endosomes are involved in the uptake of molecules from outside the cell and in their subsequent trafficking within the cells, while lysosomes are responsible for their breakdown and recycling.

The researchers found that two mouse models lacking TRPML3, which in normal conditions was mostly present in alveolar macrophages, had significantly higher MMP-12 levels in lung fluid relative to normal mice.

These TRPML3-deficient mice also showed lung damage and impaired lung function consistent with emphysema, which was further worsened when animals were exposed to tobacco smoke or elastase, an enzyme known to promote emphysema.

Further analyses in mice revealed that TRPML3 was localized at the membrane of both endosomes and lysosomes of alveolar macrophages, and that its deficiency resulted in reduced or delayed molecule uptake and trafficking within endosomes.

The ion channel was found to be necessary for MMP-12’s uptake through macropinocytosis, a type of endosomal uptake characterized by the non-specific internalization of large amounts of fluid and its molecules around the cell.

“To our surprise, we found that it is not the secretion of MMP12 that is impaired in COPD, but the endocytosis [endosome-dependent uptake],” Christian Grimm, PhD, the study’s co-senior author from the Ludwig-Maximilians University’s Walther Straub Institute of Pharmacology and Toxicology, in Munich, Germany, said in a press release.

“As such, it is not that the inflammation causes more MMP12 to be released, but that the reabsorption of excess MMP12 by TRPML3 does not work well enough,” Grimm added.

The endocytosis and trafficking defects associated with TRPML3 deficiency may result in “a backlog and congestion in the system and likely a reduced delivery of endocytosed MMP-12 to lysosomes for degradation,” the researchers wrote.

This may subsequently lead to MMP-12 accumulation in the alveoli, promoting emphysema development.

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Also, the levels of TRPML3 were found to be increased in alveolar macrophages of healthy mice exposed to tobacco smoke, as well as in the lungs of smokers versus non-smokers in two independent datasets.

This suggests that “in both smoke-exposed mice and humans, TRPML3 may be [increased] to counteract unbalanced levels of inflammatory mediators such as MMP12 via increased endocytosis,” the researchers wrote.

Smokers with COPD also showed significantly higher TRPML3 levels relative to smokers without the disease.

“Further analyses in COPD patients and smokers are needed to confirm these observations,” the researchers wrote.

Finally, treatment with a molecule that activates the TRPML3 channel was found to result in significantly lower MMP-12 levels in alveolar macrophages of healthy mice, suggesting that this type of approach may be beneficial for the treatment of COPD.

These findings “suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease,” the team concluded.