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Published in Nature Communications, a new study reveals a new signalling pathway behind macrophage inflammatory activity

Colon showing epithelial cells
Immunofluorescent staining of the colon showing epithelial cells (cyan), fibroblasts (magenta) and macrophages (green) in intestinal inflammation, provided by Dorothee Berthold, a co-author on the study.

Inflammatory bowel disease (IBD) is a group of conditions involving inflammation of the gut, that is estimated to affect 1 in 100 people in the UK. The term usually refers to two conditions – ulcerative colitis (UC) and Crohn's disease.

The exact causes of IBD are not yet known but it is understood that the protein Interferon Regulatory Factor 5 (IRF5) plays a pro-inflammatory role in in the gut during disease. A new study, published in Nature Communications, reveals a new molecular pathway in the regulation of IRF5 in macrophages, opening opportunities for new treatments to be developed for inflammatory bowel diseases and other inflammatory conditions.

Irina Udalova, Professor of Molecular Immunology at the Kennedy Institute of Rheumatology, University of Oxford explained: "IRF5 is the transcriptome factor that everyone wants to target, but no one has yet been able to. Our approach was to look at other proteins that might activate IRF5, and we found a kinase, PYK2. Both IRF5 and PYK2 are genetic risk factors for IBD, so essentially we were putting together two genetic factors in the one molecular pathway."

The team found PYK2 while screening a large collection of kinase inhibitors. They validated its functional relevance by showing that PYK2 deficient macrophages impair activation of IRF5, leading to a reduction of inflammatory gene expression. Working in collaboration with Prof Benedikt Kessler at the Target Discovery Institute, they have also mapped specific residues in IRF5 protein that PYK2 targets for phosphorylation.

Having established a link, the researchers then investigated the effect of a PYK2 inhibitor called defactinib. Currently being used in a trial for the treatment of cancer, defactinib was shown to have a similar effect on inflammatory gene expression in macrophages as IRF5 deletion itself. In collaboration with Prof Simon Travis at the Translational Gastroenterology Unit at the University of Oxford the authors applied defactinib to human colonic biopsies from UC patients and saw a significant reduction in inflammatory cytokine production.

The authors suggest that it deserves a closer look from the therapeutic perspective. "Defactinib is an attractive molecule for repurposing to treat patients with ulcerative colitis, and maybe with other inflammatory conditions where IRF5 has been implicated," said Irina.

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