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

Pun, N.; Cytlak, U. M.; Lee, D.; Domingues, R. G.; Cheadle, E. J.; Forster, D.; Williams, K. J.; Graham, G.; Hepworth, M. R.; Travis, M. A.; Illidge, T. M.; Dyer, D. P.

doi:10.1101/2024.11.05.622080

bioRxiv · 10.1101/2024.11.05.622080

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

Pun, N.·Cytlak, U. M.·Lee, D.·Domingues, R. G.·Cheadle, E. J.·Forster, D.·Williams, K. J.·Graham, G.·Hepworth, M. R.·Travis, M. A.·Illidge, T. M.·Dyer, D. P.

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Abstract

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 help regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood. Following CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of innate immune cells. Deletion of C-C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation induced toxicities, suggesting an important role for an innate immune cell population in limiting RT-mediated bowel damage. 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 found to be 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. One Sentence SummaryCCR2-mediated monocyte recruitment protects against RT-induced intestinal toxicity via IL-17, highlighting a therapeutic target.

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Pun, N., Cytlak, U. M., Lee, D., Domingues, R. G., Cheadle, E. J., Forster, D., Williams, K. J., Graham, G., Hepworth, M. R., Travis, M. A., Illidge, T. M., Dyer, D. P.. 2024-11-08. CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity. https://doi.org/10.1101/2024.11.05.622080

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