Decoding macrophage functional heterogeneity in the pathogenesis of Crohn's disease (360G-Wellcome-220725_Z_20_Z)

The accumulation of intestinal macrophages (iMφs) and presence of a distinct mononuclear phagocyte gene-expression profile, predict treatment failure and adverse clinical outcomes in Crohn's disease (CD). Preliminary scRNA-seq data demonstrates that a transcriptionally distinct iMφ subtype (CD-MΦ) accumulates in human and murine colitis, which I have prospectively validated. Unbiased CD-MΦ-epithelium, ligand-receptor interaction analyses reveals CD-MΦ derived activin signals to cognate receptors on colonic epithelium. CD-MΦs are the exclusive iMφ source of activin in mouse and humans, a TGF-β superfamily member with cell-specific cytokine, growth and hormone effects. Activin administration to human colonic epithelium inhibits proliferation with a dose- dependent effect on cytokine, chemokine and pattern recognition gene expression. Aims \- Define iMφ heterogeneity and dynamics in CD \- Interrogate the functional role of a novel pathogenic subset (CD-MΦ) in regulating intestinal inflammation \- Investigate CD-MΦ driven activin signalling as a therapeutic target for intestinal inflammation Methods Using a novel, human, biopsy-based sampling approach, I will perform scRNA-seq of iMφs in newly diagnosed, treatment naive CD patients, with longitudinal, flow cytometry- based intestinal characterisation to reveal iMφ dynamics over time. Lastly, I will manipulate cell-specific activin-signalling in transgenic animals and primary human epithelium co-culture models to probe the mechanisms of activin- mediated epithelium dysfunction in CD.