Fibrosis discovery heralds new treatment hopes

Francis Crick Institute scientists have discovered that a signaling protein called TPL-2 is crucial in preventing severe fibrosis. The research is hoped to lead to new therapies for this difficult-to-treat condition.

Mark Wilson of the Crick explained: “Fibrosis and the accumulation of extracellular matrix – the fibrous proteins and other molecules that provide structure and support around cells – is a common feature of chronic tissue injury and repair. This build-up of connective tissue is often seen during chronic infection or repeated tissue inflammation.”

“The most common types of fibrosis affect the lungs, kidneys or liver. Unfortunately, there are very few treatment options – representing a huge unmet medical need.”

Dr Wilson led a collaborative local and European-wide project to test whether the signaling molecule TPL-2, which has previously been shown to play a role in activating immune processes, contributed to the development of liver fibrosis. His group worked with Steve Ley’s and Luiz Carvalho’s groups at the Crick and with Edward Pearce’s lab at the Max Planck Institute in Germany.

The researchers worked with mice that were deficient in TPL-2 and infected them with helminth worms. Helminth infections lead to severe liver fibrosis, following tissue injury and scarring around tissue-trapped parasite eggs.

The team were surprised to discover that the mice deficient in TPL-2 developed severe liver scarring, indicating that TPL-2 prevents fibrosis. They went on to find that TPL-2 was needed for immune cells called macrophages to change their metabolic state and that this regulated inflammation and limited the build-up of extracellular matrix material. Macrophages are a type of white blood cell found at sites of inflammation or infection that engulf and digest foreign objects.

In the TPL-2-deficient mice, the macrophages failed to change their metabolic state and failed to prevent inflammation. This contributed to more extracellular matrix build-up and fibrosis.

Dr Wilson said: “These findings show that TPL-2 is an important regulator of liver fibrosis. We now need to do more research to find out exactly how TPL-2 regulates the metabolic state of macrophages and to identify new treatment avenues regulated by TPL-2 that can be targeted to prevent fibrosis.”

The paper, TPL-2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells, is published in PLoS Pathogens.