TL1A Protein and Its Receptor Drive Lung Fibrosis, Study Finds

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by Forest Ray PhD |

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A protein called TL1A drives fibrosis in diseases such as idiopathic pulmonary fibrosis (IPF), asthma, and systemic sclerosis by interacting with a receptor called DR3, a study reports.

Disrupting this interaction might prevent the formation of fibrotic tissue.

These findings are described in the study “TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling,” published in The Journal of Immunology.

“Our new study suggests that TL1A and its receptor on cells could be targets for therapeutics aimed at reducing fibrosis and tissue remodeling in patients with severe lung disease,” Michael Croft, PhD, director of scientific affairs at the La Jolla Institute for Immunology (LJI) and the study’s senior author, said in a press release.

Knowing which factors are involved in fibrosis development opens the door to potential therapies.

One molecule of interest is a cytokine, or small protein, called TL1A. Cytokines are broadly defined as cell signaling molecules; when they bind to their appropriate receptors on a cell’s surface, they signal the cell to do something — such as produce a certain protein — in response.

TL1A signals a cell to produce molecules needed for an inflammatory response by binding to its receptor, called DR3.

Researchers at LJI hypothesized that if TL1A leads to inflammation, it might contribute to fibrosis in the lungs.

The team had previously discovered that a protein closely related to TL1A could cause fibrosis when injected into the lungs of mice.

Now, they showed that delivering TL1A to mouse airways caused collagen — a protein involved in fibrosis — to accumulate and increased the smooth muscle mass in the lungs. (While a thin layer of smooth muscle in the lungs is normal and healthy, too thick of a layer causes the airway to stiffen.)

Because this was observed in mice that had the DR3 receptor but not in mice that lacked this receptor, the investigators examined what would happen in mice models of IPF with and without DR3.

The team found that IPF mice lacking DR3 receptor accumulated significantly less collagen and lung smooth muscle mass, and experienced less lung remodeling. Similarly, a compound that interfered with the interaction between TL1A and DR3 also reduced signs of fibrosis.

Further implicating TL1A-DR3 interaction in fibrosis, the investigators found that this interaction drove the expression of periostin, which has emerged as a potential biomarker of IPF.

Finally, the team discovered DR3 on the surfaces of fibroblasts — cells that play a key role in fibrosis by making and secreting collagen and extracellular matrix components. While essential to healthy tissue structure, these are also common components of fibrotic scars.

Both mouse and human fibroblasts carried the DR3 receptor. Those extracted from people with IPF and systemic sclerosis carried significantly higher levels of DR3.

“Human lung fibroblasts and bronchial epithelial cells were found to express DR3 and responded to TL1A by proliferating and/or producing fibrotic molecules such as collagen and periostin,” the researchers wrote.

Based on these results, the team suggested that “reagents that disrupt the interaction of TL1A with DR3 then have the potential to prevent deregulated tissue cell activity in lung diseases that involve fibrosis and remodeling.”

According to the team, future studies should look at which cells express DR3 in more detail, and at whether TL1A expression varies between patients.

“Our data,” the researchers concluded, “highlight an unappreciated role of TL1A/DR3 signaling as a central driver of lung fibrotic activity downstream of several inflammatory insults and suggest that TL1A and DR3 could be targets for therapeutics aimed at reducing fibrosis and tissue remodeling in humans with severe lung disease.”