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Published in Science Immunology, researchers at the Kennedy Institute have identified the role of IRF5 in controlling intestinal inflammation.

Image showing the projection of the single cell defined clusters into the tissue sections with labelling of some cells from different clusters using the antibodies against the markers that define those clusters

The term Inflammatory Bowel Disease (IBD) covers a group of debilitating inflammatory conditions of the gastrointestinal tract. Affecting 0.5 - 1% of westernised populations, patients often experience adverse side effects or become resistant to available treatments, creating a burden on healthcare systems and accelerating the need to find alternatives.

Researchers at the Kennedy Institute of Rheumatology, NDORMS have moved a step closer to understanding intrinsic mechanisms behind intestinal inflammation. They had previously understood the role that the protein Interferon Regulatory Factor 5 (IRF5) had in establishing the inflammatory state of macrophages, innate immune cells often involved in initiating inflammation. Tissue macrophages come in many different shapes and flavours, but during inflammation a large proportion of them are created by monocytes in the blood stream entering the tissue and differentiating into macrophages. Researchers wanted to understand whether IRF5 may play a role in controlling macrophage differentiation and function in tissue.

Led by Irina Udalova, Professor of Molecular Immunology, the research team began by analysing a role for IRF5 in shaping monocyte-macrophage system in the gut, in collaboration with Fiona Powrie. Using the model of helicobacter hepaticus-induced colitis they first found that a deficiency of IRF5 was protective against the development of colitis and that macrophages played a major role.

Keen to understand more specific aspects of macrophage development, they then used a combination of mixed bone marrow chimaera and a new technology called single cell gene expression analysis. "Teaming up with Stephen Samson's computational genomics group, we looked at the single cell analysis of the monocyte-macrophage system. We were able to see how cells that have or lack IRF5 behave in a shared environment, and whether they take different routes in their development," said Irina.

They discovered that there are specific populations of inflammatory macrophages that are affected by IRF5, and other macrophages that are less affected. When IRF5 is absent there is a targeted reduction of that specific inflammatory phenotype, that helps to resolve colitis.

"This is a truly collaborative study by the Kennedy research groups that once again highlights IRF5 as a major target for drug development in inflammatory diseases. The next step needs to explore ways to alter IRF5 expression or its activation for therapeutic applications,' said Irina.

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