Can blocking ‘danger signals’ reduce inflammation in the bowel?


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We hope our work will take us one step closer to a new treatment in IBD

Dr Gwo-Tzer Ho
MRC Centre for Inflammation Research 

What is this research looking at? 

Mitochondria are tiny structures found in cells that act as ‘power stations,’ providing the energy that cells need to survive.  Mitochondria evolved from bacteria about 2-3 billion years ago, and therefore there are many similarities between them, such as both containing their own DNA.  When cells are damaged, mitochondria and their contents can be released.  When immune cells that protect the body from harmful invaders come into contact with released mitochondria, they confuse them with bacteria.  This activates the immune cells, and causes a prolonged inflammatory response and damage to the body’s own tissue.  Mitochondria therefore act as a ‘danger signal’ to the immune system, coming from the body itself. 

In a recently completed project funded by Crohn’s and Colitis UK, these researchers showed that cells in parts of the bowel affected by IBD become injured and leak mitochondrial DNA (mtDNA) as a danger signal.  Leaked mtDNA is recognised by a sensor called Toll-like receptor 9 (TLR9).  Many studies have shown that activation of TLR9 by mtDNA is highly inflammatory.  TLR9 is present in the lining of the bowel and in immune cells.  When the researchers removed the TLR9 gene in mice, they showed that this significantly reduced experimental mouse Colitis.  This shows that TLR9 recognising mtDNA is important in bowel inflammation. 

In this follow-on project, the researchers will gather scientific information in three key areas: 

  1. They aim to confirm that mtDNA from parts of the bowel affected by IBD can trigger a greater inflammatory response than in the unaffected bowel from the same individuals with IBD, and from individuals without IBD. 
  2. They will study different drugs that can block this inflammatory response. 
  3. They will investigate the beneficial effect of blocking the mtDNA danger signal in two important types of inflammatory cells that express TLR9, in people with and without IBD. 

The researchers seek direct proof that blocking mtDNA danger signals can effectively reduce inflammation in the bowel.  They hope to plan further studies to search for new drugs that can block this specific pathway to inflammation. 

What do researchers think this could this mean for people with IBD?  

Researchers hope the data from this project will identify a new approach to treatment, based on blocking the inflammatory effects of mtDNA.  They think this kind of treatment may apply to people with a severe active flare, or those with IBD that shows little or no healing of the bowel after treatment with anti-inflammatory or immunosuppressive therapies.  This new treatment would block specific signals that activate the immune cells, instead of decreasing the function of them, which is how immunosuppressive treatment works. 

Who is leading this research:  Dr Gwo-tzer Ho, MRC Centre for Inflammation Research 
Our Funding: £118,767 
Duration: 24 months 
Official title of application: Blocking gut danger signals as treatment for inflammatory bowel disease