ӳ����ý

When inflammation in the body goes unchecked, it can cause fibrosis, or tissue scarring that may lead to organ dysfunction or even failure. This can happen in conditions such as inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), chronic viral infections, interstitial lung fibrosis, chronic autoimmune skin diseases such as scleroderma, and scars associated with heart disease. Patients have few options for treating fibrosis, but new research points to a molecular pathway that could open the door to future treatment possibilities.

In earlier work, a team led by researchers at the ӳ����ý and Mass General Brigham discovered a key cell type underlying fibrosis in inflammatory bowel disease (IBD). Now, in a new study in , the team has characterized the crosstalk between this and other types of cells that leads to fibrosis. Their work also points to a molecule, GLIS3, that regulates this cell-to-cell communication and hadn’t been linked to IBD before. The findings suggest that interrupting this cellular pathway could one day help prevent or reduce fibrosis in patients with IBD or other diseases marked by chronic inflammation such as lung disease. 

“Anywhere we see chronic inflammation, fibrosis is a major issue,” said study co-senior author Ramnik Xavier. “There aren't any treatments or therapeutics to directly address fibrosis, so there’s much room to make progress and improve health for patients with chronic inflammatory disease.” Xavier is also a ӳ����ý core institute member and the director of ӳ����ý’s Klarman Cell Observatory, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital.

Listening in on cellular crosstalk

Scientists in the Xavier lab have worked for years to unravel the roots of pathological inflammatory responses in patients with IBD, taking clues from large-scale genetic studies and experiments in the lab. Previously, they found a type of cell called the inflammation-associated fibroblast that is important in IBD, but they didn’t fully understand how it leads to tissue damage. 

“The more we’ve learned about the process of inflammation, the more we began to appreciate the roles of non-immune cell types in these pathologies, in particular, communication between immune cells and structural cells in the tissue like fibroblasts,” said study co-senior author Daniel Graham, senior director of functional genomics in the Infectious Disease and Microbiome Program at the ӳ����ý, where he is also an institute scientist. 

In the new study, the researchers used single-cell and spatial approaches to map individual cells in intestinal samples from patients with IBD. They tracked down the inflammation-associated fibroblasts in the samples and examined the surrounding cellular neighbors. The patients’ fibroblasts were often found with inflammatory macrophages, an immune cell type. The fibroblasts appeared to be churning out a protein called IL-11, which helps deposit scar-like tissue. 

Through gene expression analysis and experiments in the lab, the researchers determined that the fibroblasts make IL-11 in response to two substances, TGF-beta and IL-1, produced by the nearby macrophages. Next, project lead Vlad Pokatayev performed CRISPR screening to test for genes necessary for the fibroblasts to make IL-11, and discovered that GLIS3, a transcription factor known for its role in insulin production and thyroid hormone regulation, is a master regulator of the messaging between macrophages and fibroblasts that leads to fibrosis.

Further testing showed that animals without GLIS3 don’t develop fibrosis after bowel inflammation. The scientists also found more GLIS3 activity in patients with more severe disease, adding to the evidence of its role in fibrosis.

These findings suggest that this network of cells and the GLIS3 pathway could be viable targets for developing new treatments. They also suggest that small molecules and biologics currently in clinical development aimed at neutralizing IL-11 may have potential in IBD. The team says these and other medicines that target this pathway could potentially be used in addition to existing IBD therapies, to treat both the inflammation and its complications such as fibrosis.

ӳ����ý researchers in collaboration with clinical investigators at Mass General Brigham are continuing to explore how GLIS3 is regulated and the roles of these cells in not only IBD, but also other inflammatory and autoimmune diseases. “Now that we understand this core pathway mediated by GLIS3, the targets that regulate this pathway are potentially viable for treating some of these other fibrotic diseases as well,” said Graham.