CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity

Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood. CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of immune cells. Deletion of C-C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation induced toxicities. Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C+ monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was reduced in irradiated CCR2-/-, however the transfer of Ly6C+ monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities.</jats:p>