Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal disease in which repeated or poorly repaired lung injury leads to irreversible scarring. Now, a study done in mice shows that TLR5, an immune sensor that detects a bacterial protein, protects injured lungs from scarring.

The findings, published in Science Translational Medicine, suggest that targeting TLR5 could offer a new way to treat or prevent IPF by correcting harmful lung microbiota changes after injury.

Previous work has linked altered lung microbial communities with IPF, but it is unclear whether specific host genes help shape the lung microbiota after injury. 

Because TLR5 has been linked to airway infection risk, researchers led by Yosuke Sakamachi at the National Institute of Environmental Health Sciences in Durham, North Carolina, studied whether this immune sensor could affect IPF too.

Immune sensor

In people, a TLR5 variant that weakens signaling was associated with higher IPF risk. In the lungs, TLR5 is present in epithelial and immune cells, and it appeared in regions involved in fibrosis in people with IPF. 

People with the TLR5 variant had altered lung microbiotas, with more Proteobacteria and less Bacteroidetes. They also showed increases in microbes such as Haemophilus, Staphylococcus, and Neisseria as well as a decrease in Prevotella. 

Compared to mice with normal TLR5, mice lacking TLR5 had more collagen buildup, worse tissue scarring, more lung injury, greater weight loss, and poorer survival. These animals also had less diverse lung microbial communities after injury, with more Proteobacteria and Gammaproteobacteria, the researchers found. 

Lung protection

When mice were treated with GP532, a compound that activates TLR5, they showed reduced lung injury, tissue scarring, weight loss, and mortality. However, the treatment did not work in mice lacking TLR5, suggesting that the protective effect depends on this receptor. The researchers also found that the protective effect of TLR5 was reduced when microbes were depleted with antibiotics. 

Activating TLR5 in lung epithelial cells switched on antimicrobial defense genes and protected mice from severe lung scarring, the researchers also found. 

“TLR5 protects against pulmonary fibrosis through effects on the lung microbiota, providing insight into therapeutic approaches that may ultimately benefit patients with IPF,” they say.