Protein discovery raises prospect of treatment for COPD
A new study has found that TLR7, a protein that normally triggers our immune system to defend against certain viruses, plays a pivotal role in exacerbating chronic obstructive pulmonary disease or COPD. The unexpected discovery may lead to new therapeutic approaches for the incurable condition.
COPD, sometimes called emphysema, is often caused by cigarette smoking or exposure to irritants. It can destroy the lung’s air sacs and cause inflammation and the production of excessive mucus, making breathing difficult. COPD is incurable; treatment includes the management of symptoms.
Researchers from the Centenary Institute and the University of Technology Sydney have led a study into the mechanisms underlying the exacerbation of COPD and found that the protein Toll-like receptor 7 (TLR7), which helps defend our bodies against certain types of virus, plays a pivotal, and unexpected, role.
“Surprisingly, our research shows heightened TLR7 levels in individuals with COPD and also in experimental COPD models involving mice,” said Gang Liu, lead author of the study. “The preclinical findings shed light on TLR7’s unexpected role in aggravating lung conditions.”
The TLR family of proteins plays an important role in pathogen recognition and the activation of innate immunity. TLR7 recognizes single-stranded RNA viruses such as those responsible for measles, influenza and hepatitis C.
The researchers examined transcriptomes in lung biopsies taken from healthy and COPD donors at various stages of disease severity. They identified 4,269 differentially expressed genes of three gene clusters linked to immune response, tissue remodeling, and metabolic reprogramming. TLR7 was part of the immune response cluster that was over-expressed in COPD.
“This is unexpected because the known roles of TLR7 are in antiviral immunity and protection against infection-induced exacerbations in respiratory diseases,” the researchers said.
Mice genetically altered to be deficient in the TLR7 protein and exposed to cigarette smoke equivalent to that inhaled by a pack-a-day smoker were observed to have less emphysema and airway remodeling, improved lung function, and less apoptosis, or programmed cell death, in the lungs. Administering the drug imiquimod, which is known to activate TLR7, to healthy but cigarette-smoke-exposed mice resulted in an exacerbation of lung issues.
Significantly, the researchers found that TLR7-positive mast cells were increased in COPD patients. Due to their location in the skin and mucosa, including human lung tissue and the bronchi, mast cells are the first line of defense against antigens entering the body. Further, they found that increased TLR7-positive mast cell numbers correlated with lung function impairment, indicating an association between mast cells and COPD severity.
“Mast cells play a significant role in worsening COPD by initiating and perpetuating inflammation within the fragile lung tissues, making it harder for people to breathe,” Liu said. “We found that higher TLR7 levels increase mast cell activity, escalating lung problems.”
The researchers hope that their findings will lead to treatments for COPD.
“Blocking TLR7 with targeted drugs could be a promising new therapeutic approach for COPD, a challenging lung condition which currently has no cure,” said Liu.
The study was published in the journal Nature Communications.
Source: Centenary Institute