#IDIBELLseminars: Tissue-resident macrophages are essential for epithelial regeneration after radiotherapy-induced salivary gland injury

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in xerostomia, or chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages have long been considered key cells in the tissue repair process and are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. We have shown that macrophages are the predominant immune cell type in the murine salivary glands, and via a combination of mutant mice and antibody blockade, we have demonstrated that salivary gland macrophages are dependent on CSF1 for their development and maintenance. Using an in vivo model of radiation-induced salivary gland injury combined with either a novel genetic depletion system or an antibody blockade approach, we show that in the absence of macrophages effective tissue repair following such injury is severely comprised and salivary gland function is impaired. Via in vivo analysis and ex vivo live cell imaging we have shown that macrophages intimately associate with progenitor cells after injury. Furthermore, using our recently generated scRNAseq data and CellChat, a tool that is able to quantitatively infer and analyse intercellular communication networks, we have shown that there are direct interactions between progenitor cells and macrophages. Using a novel dual reporter mouse, we have confirmed that progenitor cells and macrophages communicate via ligand receptor interactions providing robust evidence that macrophages directly communicate with progenitor cells during the repair process. Finally, we have shown that in the absence of macrophages progenitor cell-mediated regeneration fails to occur. Our data highlight the bidirectional communication between macrophages and epithelial cells in the salivary gland and demonstrate the pivotal role that macrophages play during epithelial repair. Overall, this indicates a strong case for exploring the therapeutic potential of manipulating macrophages in order to promote tissue repair and thus minimise salivary gland dysfunction after radiotherapy.

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in xerostomia, or chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages have long been considered key cells in the tissue repair process and are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. We have shown that macrophages are the predominant immune cell type in the murine salivary glands, and via a combination of mutant mice and antibody blockade, we have demonstrated that salivary gland macrophages are dependent on CSF1 for their development and maintenance. Using an in vivo model of radiation-induced salivary gland injury combined with either a novel genetic depletion system or an antibody blockade approach, we show that in the absence of macrophages effective tissue repair following such injury is severely comprised and salivary gland function is impaired. Via in vivo analysis and ex vivo live cell imaging we have shown that macrophages intimately associate with progenitor cells after injury. Furthermore, using our recently generated scRNAseq data and CellChat, a tool that is able to quantitatively infer and analyse intercellular communication networks, we have shown that there are direct interactions between progenitor cells and macrophages. Using a novel dual reporter mouse, we have confirmed that progenitor cells and macrophages communicate via ligand receptor interactions providing robust evidence that macrophages directly communicate with progenitor cells during the repair process. Finally, we have shown that in the absence of macrophages progenitor cell-mediated regeneration fails to occur. Our data highlight the bidirectional communication between macrophages and epithelial cells in the salivary gland and demonstrate the pivotal role that macrophages play during epithelial repair. Overall, this indicates a strong case for exploring the therapeutic potential of manipulating macrophages in order to promote tissue repair and thus minimise salivary gland dysfunction after radiotherapy.