A new study finds that TLR7 - a protein that normally triggers our immune system to fight off certain viruses - plays a key role in the progression of chronic obstructive pulmonary disease (COPD). The unexpected discovery could lead to new treatments for this incurable disease.
COPD, sometimes called emphysema, is often caused by smoking or exposure to irritants. It damages the air sacs in the lungs, causing inflammation and excessive mucus production, making it difficult to breathe. There is no cure for COPD, and treatment includes managing symptoms.
Researchers from the Centenary Institute and the University of Technology Sydney have studied the mechanisms by which chronic obstructive pulmonary disease worsens and found that a protein called Toll-like receptor 7 (TLR7), which helps the body fight off certain types of viruses, plays an unexpected key role.
Gang Liu, the first author of the study, said: "Surprisingly, our study showed that TLR7 levels are elevated in patients with COPD, but also in experimental models of COPD involving mice. The preclinical findings reveal an unexpected role for TLR7 in exacerbating lung disease."
TLR family proteins play an important role in pathogen recognition and activation of innate immunity. TLR7 recognizes single-stranded RNA viruses, such as those that cause measles, influenza and hepatitis C.
The researchers studied the transcriptomes of lung biopsies from healthy donors and COPD donors at different stages of disease severity. They found 4,269 differentially expressed genes in three gene clusters related to immune response, tissue remodeling and metabolic reprogramming. TLR7 is part of a cluster of immune response genes that are overexpressed in chronic obstructive pulmonary disease.
"This was unexpected, as TLR7's known role is in antiviral immunity and preventing the exacerbation of respiratory disease caused by infection," the researchers said.
The researchers observed that mice genetically modified to lack the TLR7 protein experienced reduced emphysema and airway remodeling, improved lung function, and reduced apoptosis, or programmed cell death, in the lungs when exposed to the equivalent of cigarette smoke inhaled by a pack-a-day smoker. Giving imiquimod, a drug known to activate TLR7, to healthy mice exposed to cigarette smoke caused lung problems to worsen.
Notably, the researchers found an increase in TLR7-positive mast cells in patients with COPD. Because they are located in the skin and mucous membranes, including human lung tissue and bronchi, mast cells are the first line of defense against antigens entering the body. Additionally, they found that increased numbers of TLR7-positive mast cells were associated with impaired lung function, suggesting that mast cells are involved in the severity of COPD.
"Mast cells play an important role in the progression of COPD, initiating and perpetuating inflammation in fragile lung tissue and making it more difficult for people to breathe," Liu said. "We found that higher TLR7 levels increase mast cell activity and worsen lung problems."
The researchers hope their findings could lead to treatments for COPD.
"Blocking TLR7 with targeted drugs may be a promising new treatment for chronic obstructive pulmonary disease, a challenging lung disease that currently has no cure," Liu said.
The research was published in the journal Nature Communications.