Targeting C5aR1 Reveals Protective Macrophage Maturation States in Intestinal Injury

Inflammatory intestinal injury, which may occur following cytotoxic cancer treatments such as radiotherapy, compromises homeostasis when intestinal stem cells undergo apoptosis and regeneration programmes are not effectively engaged. Recent evidence indicates the importance of macrophages in regulating stem regeneration following injury, but how to therapeutically promote specific macrophage subtypes which may tip the balance away from apoptosis and towards regeneration is still unclear. Here we show that targeting complement C5a receptor 1 (C5aR1) reduces radiation-induced intestinal injury by promoting macrophage phenotypes which reduce intestinal stem cell apoptosis. Specifically, C5aR1 signalling attenuates a macrophage maturation response characterised by increased IL10 and CX3CR1 expression. Our data indicate that increased IL10 signalling, and macrophage maturation induced following C5aR1 targeting are important for regulating crypt cell loss via radiotherapy-induced apoptosis. Interestingly, IL10-signalling is also critical for the improved tumour radiation response observed following C5aR1 targeting.