Switching on tissue repair in IBD

Switching on tissue repair in IBD

  • In inflammatory bowel disease (IBD), the immune system attacks the cells that form the lining of the gut. This causes pain and discomfort.
  • In a new study, scientists have identified a type of immune cell that can initiate repair of the gut lining following inflammation.
  • Importantly, they have discovered a way to switch the cells from promoting inflammation to promoting repair.

The Centers for Disease Control and Prevention (CDC) estimate that in 2015, 3.1 million people in the United States had IBD.

IBD is an umbrella term for a number of conditions, including ulcerative colitis and Crohn’s disease. It is not the same as irritable bowel syndrome, which does not cause inflammation.

Some common symptoms of IBD include:

  • abdominal pain
  • persistent diarrhea
  • rectal bleeding or bloody stools
  • weight loss
  • fatigue

Experts are still not sure what causes IBD, but they know the condition involves the immune system attacking tissues that line the gut, even though there is no infection. This autoimmune response causes inflammation and ulceration of the gut lining.

Treatments such as corticosteroids can reduce this inflammatory response. However, in the process, they can also inhibit other parts of the immune system involved in repairing damaged tissue.

In particular, immune cells called macrophages play a role in both inflammation and healing of the intestinal lining. Macrophages can ingest cellular debris and microorganisms, but they also release signaling molecules that initiate inflammatory or repair processes.

The molecular mechanism that flips them from inflammatory mode to repair mode has been a mystery, however.

Molecular master switch

Researchers at KU Leuven in Belgium and Seoul National University in the Republic of Korea set out to discover this molecular “master switch.” They started by investigating macrophages in the intestines of people with IBD.

When the participants were experiencing a flare-up of their condition, the scientists found that they had low numbers of a particular type of macrophage in their gut, compared with individuals who do not have IBD.

When their condition went into remission, however, these macrophages increased in number.

The cells in question had receptors in their membrane for a hormone-like signaling molecule called prostaglandin E2 (PGE2), which is associated with tissue regeneration.

“If the [participants] had acute disease, they had a lower amount of these beneficial cells, and if they went into remission, then amounts of macrophages went up,” says lead study author Prof. Gianluca Matteoli, an immunologist at the Translational Research Center for Gastrointestinal Disorders at KU Leuven.

“This suggests that they are part of the reparative process,” he adds.

The scientists report their findings in the journal Gut.

Animal model

Next, the researchers investigated the equivalent type of macrophage in a mouse model of ulcerative colitis, which is one form of IBD.

They discovered that cells with receptors for PGE2 were few and far between in animals with the condition. However, when the scientists increased levels of PGE2 in the animals’ guts, these cells responded by releasing a substance called CXCL1, which promotes tissue regeneration.

To confirm that PGE2 receptors are responsible for switching macrophages from inflammatory mode to healing mode, the researchers created mice whose bodies were unable to make the receptor.

As the scientists predicted, these mice struggled to repair the cells lining their gut.

In a final experiment, the researchers restored the macrophages’ powers of healing by providing a drug that stimulated the cells to make CXCL1.

They delivered this drug inside artificial spherical vesicles called liposomes, which the macrophages ingested.

“We already knew that prostaglandins were important for inducing proliferation of tissue cells, but this study shows that they are also important for controlling the inflammatory effect, so moving the body from the acute stage where inflammation dominates to the reparative stage.”

– Prof. Gianluca Matteoli

Drug delivery system

Study co-author Prof. Seung Hyeok Seok led a team at Seoul National University that created the drug delivery system.

The researchers are planning more detailed investigations into the types of human macrophage involved at different stages of IBD. Their long-term goal is to design drugs that will turn off inflammation and promote tissue repair.

“We want to identify other factors that trip the switch that turns macrophages from inflammatory cells to non-inflammatory cells,” says Prof. Matteoli. “Then, using the liposome technology that Prof. Seok has developed, these could be used to target the macrophages and so produce very precise drugs.”

In their paper, the researchers conclude:

“Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favor remission in [people] with IBD.”

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