Targeting molecular switches in specialized lung cells may provide a new approach to preventing complications from allergic airway diseases.
RT’s Three Key Takeaways:
- Club Cell Regulation: Researchers identified that the protein RhoA acts as a molecular switch in club cells to regulate airway inflammation triggered by allergens.
- Epithelial Barrier Protection: Study models showed that deficient RhoA expression helped maintain the integrity of the lung epithelial barrier, which typically breaks down in patients with asthma.
- Potential Therapeutic Target: The identification of the cytokine CCL24 as a mediator controlled by RhoA provides a specific target for future asthma treatments and clinical studies.
Johns Hopkins Medicine researchers identified molecular pathways controlled by the protein RhoA in club cells that could be selectively targeted to potentially prevent asthma-related complications, according to a study published in the Journal of Allergy and Clinical Immunology,
They research utilized translational mouse models and 3D cell cultures to examine how RhoA operates in club cells. These specialized epithelial cells line the small airways of the lungs and are known to play roles in airway repair and immune regulation.
Asthma is a chronic inflammatory disease that causes airway narrowing and symptoms such as wheezing and shortness of breath, affecting 8.2% of adults and children in the US, according to the CDC. While the causes of asthma are not fully understood, the research team sought to clarify the molecular mechanisms responsible for airway inflammation.
Peisong Gao, MD, PhD, a professor of medicine at the Johns Hopkins University School of Medicine and corresponding author of the study, noted that RhoA expression has previously been linked to worsening asthma. However, his earlier research found that removing the protein can worsen inflammation in certain other lung cell populations.
To understand its specific role in club cells, the team created a RhoA “knockout” mouse model that did not express the protein in those cells. When exposed to cockroach allergens, the RhoA-deficient mice showed fewer inflammatory cytokines and immune cells compared to a control group.
The researchers also compared 3D lung cell cultures designed to replicate the lung epithelial barrier. In patients with asthma, the dysfunction of this barrier contributes to tissue damage and worsening symptoms over time.
“Unlike the control group, RhoA-deficient cultures retained typical epithelial barrier integrity and function,” the researchers said in a news release.
Using flow cytometry and RNA-sequencing, the team discovered that RhoA expression regulates a major immune cell population known as interstitial macrophages. They specifically identified CCL24, a cytokine that promotes inflammation, as being suppressed in the cells lacking RhoA.
The study found that treating allergen-exposed mice with a CCL24-neutralizing antibody stopped airway inflammation. This finding suggests that targeting the gene pathways regulated by RhoA could allow for the control of immune activity without directly targeting the protein itself.
“As the prevalence of asthma continues to increase, our findings, especially identification of the RhoA-controlled CCL24 as a key inflammation mediator in club cells, are critical because they provide a list of potential mediators that could be targeted for future asthma studies or as future asthma treatments,” said Gao, in a news release.
The research was supported by grants from the National Institutes of Health (NIH). The team plans to conduct further experiments to explore how CCL24 mediates immune activity in the lungs.
