Dr Gwo-tzer Ho (IBD)
Institution: University of Edinburgh
Title: Resolving Inflammation in IBD: Developing a new therapeutic approach by targeting pro-inflammatory mitochondrial formylated petides on neutrophil FPR1-pathway
Project Start Date: 1 February 2019
Completion Date: 1 January 2021
Inflammation is a normal beneficial response to tissue injury. For example, the skin becomes inflamed after a cut but then, it heals. In Inflammatory Bowel Diseases (IBD), we do not know why the gut becomes and remains continuously inflamed. Such a pattern of chronic inflammation becomes destructive and leads to long term damage of the bowel. Our recent studies have shown that the affected bowel tissue in IBD release ‘danger signals’ or damage-associated molecular patterns (DAMPs) that may be an important factor in why gut inflammation in IBD does not improve and persists.
In this study, we are particularly interested in ‘danger signals’ arising from the mitochondria. Mitochondria are the ‘batteries’ or ‘powerstations’ that reside within, and provide energy for living cells. They have evolved from bacteria around 2-3 billion years ago. As such the mitochondria have many similarities with bacteria. When our immune cells encounter mitochondria that are released, they confuse them with bacteria, become activated and trigger a prolonged inflammatory response, which is destructive to our own tissue.
Of interest, we have recently shown that fragments of mitochondria, called formylated peptides can be found at high levels in the blood stream during a severe flare of disease. These fragments are very similar to bacterial proteins and are known to attract and make immune cells become inflammatory by activating a cell receptor called formylated peptide receptor-1 (FPR1).
We have already shown that immune cells in the gut have very high FPR1 in UC and Crohn’s disease; and in mouse, removal of the FPR1 gene is beneficial in experimental mouse colitis. We think that these particular fragments are leaked into the bloodstream of IBD patients from the damaged gut cells. Here, they act as a signal that attracts immune cells to the affected gut. Hence the FPR1 that acts as our body’s ‘alarm system’ against bacteria, is also triggered by our own mitochondria leading to the situation where gut inflammation cannot improved – ‘the alarm cannot be switched off’.
In this study, we aim to directly test the importance of this group of mitochondrial formylated peptides as an inflammatory signal in the bloodstream of individuals with IBD. We will study participants with newly diagnosed IBD (and not on any current treatments) and test the ability of their blood to activate and attract immune cells. We will then block this response using an experimental drug that blocks FPR1-receptor. This data will then be used to make better drugs that are even more specific that may eventually lead to clinical use in IBD.
Secondly, we will accurately study the usefulness of blood levels of mitochondrial formylated peptides in our larger IBD population (around 300 IBD patients and 150 healthy controls, most of which we have already obtained their blood samples from recent studies). Importantly, they will be from adults and children with IBD. Here we think we can find a group of patients with very blood levels of mitochondrial formylated peptides where our future treatments can be especially useful for (fitting with the idea of ‘personalised medicine’.
Hence, rather than suppressing the immune system, we plan to develop a treatment that is aimed at healing and return the bowel wall to a normal state in both adults and children with IBD.
We are really grateful to Guts Charity UK funding that will enable us to explore a potentially new way of treatment by switching off the ‘alarm signal’ that attracts inflammatory cells to the gut wall in IBD.Dr HO Gwo-tzer