IL-1 generated subsequent to radiation-induced tissue injury contributes to the pathogenesis of radiodermatitis

Abstract

Radiation injury in the skin causes radiodermatitis, a condition in which the skin becomes inflamed and the epidermis can break down. This condition causes significant morbidity and if severe it can be an independent factor that contributes to radiation mortality. Radiodermatitis is seen in some settings of radiotherapy for cancer and is also of concern as a complication post-radiation exposure from accidents or weapons, such as a "dirty bomb". The pathogenesis of this condition is incompletely understood. Here we have developed a murine model of radiodermatitis wherein the skin is selectively injured by irradiation with high-energy electrons. Using this model we showed that the interleukin-1 (IL-1) pathway plays a significant role in the development of radiodermatitis. Mice that lack either IL-1 or the IL-1 receptor developed less inflammation and less severe pathological changes in their skin, especially at later time-points. These findings suggest that IL-1 pathway may be a potential therapeutic target for reducing the severity of radiodermatitis.

FIG. 1

Clinical evaluation of radiodermatitis as a function of radiation dose. The skin of the right flank of C57BL6 mice was exposed to the indicated doses of radiation and then evaluated clinically over time. Fifty percent of C57BL6 wild-type mice receiving 2,000 cGy to right flank skin developed grade 4 skin damage 30 days after exposure. Animals were sacrificed if they developed a skin score of 4 (ulceration). The number of surviving animals over time is shown at the top of the graph. Data are shown as mean values ± SEM.

FIG. 2

Gross photographs demonstrate different skin changes after ionizing radiation exposure in C57BL6 mice. Panel A: Normal-appearing skin, score 0; panel B: erythema, score 1; panel C: dry desquamation, score 2; panel D: wet desquamation, score 3; and panel E: ulceration, score 4.

FIG. 3

Course of radiodermatitis in wild-type versus IL-1R1-deficient mice. Skin of C57BL6 and IL-1R-deficient mice was exposed to 2,175 cGy ionizing radiation and changes were recorded over time by clinical observation (panel A) and bioluminescence monitoring (panel B). Animals were sacrificed if they developed a skin score of 4 (ulceration). The number of surviving animals over time is shown at the top of the graph. Data are shown as mean values ± SEM (representative experiment).

FIG. 4

(Immuno)histological images irradiated skin. Photomicrographs of skin sections from representative wild-type (panels A, C, E) or IL-1R1^−/− (panels B, D, F) mice exposed to 2,000 cGy. Panels A–D were stained with H&E or with anti-CD31 (panels E, F) either 2 weeks (panels A, B) or 3 weeks (panels C, D) post-irradiation. Magnification is 20× for the main images, and 10× for the insets in panels A and B, and 4× for the insets in panels C and D.

FIG. 5

Course of radiodermatitis in wild-type versus IL-1 deficient mice. Skin of C57BL6 and IL-1-deficient mice was exposed to 2,000 cGy ionizing radiation and changes were recorded over time by clinical observation. Animals were sacrificed if they developed a skin score of 4 (ulceration). The number of surviving animals over time is shown at the top of the graph. Data are shown as mean values ± SEM.