Acute Innate Immune Response Profiles Following Cranial Irradiation

Purpose/Objective(s)Cranial irradiation (CI) is commonly used in the treatment of either primary or metastatic intracranial lesions, and dose per fraction strategies range from standard to hypofractionated and single fraction schedules. The purpose of this study was to examine in a preclinical murine model the differential effects of low- vs high-dose per fraction in the intracranial innate inflammatory response elicited by CI.Materials/MethodsAdult C57BL/6J mice were anesthetized and treated with 2 Gy, 21 Gy or sham CI using an X-ray irradiator. Mice were humanely euthanized 24 h later and whole brains were harvested for multicolor flow cytometric analysis of intracranial cellular populations. Based on surface marker phenotypic profiles, the fold change in microglial, brain dendritic cells, and innate phagocytic populations were characterized.ResultsA dose-dependent reduction in the population of microglial and brain dendritic cells was observed. Single fraction 21 Gy resulted in similar 88% and 82% reductions of the baseline microglial and brain dendritic cell populations, respectively. However, single fraction 2 Gy had a more profound eradicating effect on microglial cells (60% reduction) than brain dendritic cells (10% reduction). A CD11b+ innate phagocytic population increased in intracranial frequency following high-dose CI (1.6 to 2.8-fold change from baseline), but this potential peripheral recruitment into the irradiated brain was not observed when low-dose CI was used. Three particular subsets of CD11b+CD45+ populations that are recruited to the brain in a viral encephalitis model to facilitate adaptive immunity were also observed to fluctuate in levels following the CI insults.ConclusionsOur preliminary data suggest that the dose per fraction used for CI has, as expected, a differential effect on toxicity against intracranial microglial and brain dendritic cell populations following a single fraction, with the higher dose resulting in greater toxicity. However, peripheral recruitment or differentiation of CD11b+ innate phagocytic populations may be better facilitated by SRS-range doses, with the effect observed acutely within 24 h. Efforts to further understand the acute innate immune response elicited by CI are underway, and the findings could guide efforts in different models for inflammatory modulation resulting in either enhanced antitumor immunity or decreased risk of CI-induced sequelae such as radionecrosis. Purpose/Objective(s)Cranial irradiation (CI) is commonly used in the treatment of either primary or metastatic intracranial lesions, and dose per fraction strategies range from standard to hypofractionated and single fraction schedules. The purpose of this study was to examine in a preclinical murine model the differential effects of low- vs high-dose per fraction in the intracranial innate inflammatory response elicited by CI. Cranial irradiation (CI) is commonly used in the treatment of either primary or metastatic intracranial lesions, and dose per fraction strategies range from standard to hypofractionated and single fraction schedules. The purpose of this study was to examine in a preclinical murine model the differential effects of low- vs high-dose per fraction in the intracranial innate inflammatory response elicited by CI. Materials/MethodsAdult C57BL/6J mice were anesthetized and treated with 2 Gy, 21 Gy or sham CI using an X-ray irradiator. Mice were humanely euthanized 24 h later and whole brains were harvested for multicolor flow cytometric analysis of intracranial cellular populations. Based on surface marker phenotypic profiles, the fold change in microglial, brain dendritic cells, and innate phagocytic populations were characterized. Adult C57BL/6J mice were anesthetized and treated with 2 Gy, 21 Gy or sham CI using an X-ray irradiator. Mice were humanely euthanized 24 h later and whole brains were harvested for multicolor flow cytometric analysis of intracranial cellular populations. Based on surface marker phenotypic profiles, the fold change in microglial, brain dendritic cells, and innate phagocytic populations were characterized. ResultsA dose-dependent reduction in the population of microglial and brain dendritic cells was observed. Single fraction 21 Gy resulted in similar 88% and 82% reductions of the baseline microglial and brain dendritic cell populations, respectively. However, single fraction 2 Gy had a more profound eradicating effect on microglial cells (60% reduction) than brain dendritic cells (10% reduction). A CD11b+ innate phagocytic population increased in intracranial frequency following high-dose CI (1.6 to 2.8-fold change from baseline), but this potential peripheral recruitment into the irradiated brain was not observed when low-dose CI was used. Three particular subsets of CD11b+CD45+ populations that are recruited to the brain in a viral encephalitis model to facilitate adaptive immunity were also observed to fluctuate in levels following the CI insults. A dose-dependent reduction in the population of microglial and brain dendritic cells was observed. Single fraction 21 Gy resulted in similar 88% and 82% reductions of the baseline microglial and brain dendritic cell populations, respectively. However, single fraction 2 Gy had a more profound eradicating effect on microglial cells (60% reduction) than brain dendritic cells (10% reduction). A CD11b+ innate phagocytic population increased in intracranial frequency following high-dose CI (1.6 to 2.8-fold change from baseline), but this potential peripheral recruitment into the irradiated brain was not observed when low-dose CI was used. Three particular subsets of CD11b+CD45+ populations that are recruited to the brain in a viral encephalitis model to facilitate adaptive immunity were also observed to fluctuate in levels following the CI insults. ConclusionsOur preliminary data suggest that the dose per fraction used for CI has, as expected, a differential effect on toxicity against intracranial microglial and brain dendritic cell populations following a single fraction, with the higher dose resulting in greater toxicity. However, peripheral recruitment or differentiation of CD11b+ innate phagocytic populations may be better facilitated by SRS-range doses, with the effect observed acutely within 24 h. Efforts to further understand the acute innate immune response elicited by CI are underway, and the findings could guide efforts in different models for inflammatory modulation resulting in either enhanced antitumor immunity or decreased risk of CI-induced sequelae such as radionecrosis. Our preliminary data suggest that the dose per fraction used for CI has, as expected, a differential effect on toxicity against intracranial microglial and brain dendritic cell populations following a single fraction, with the higher dose resulting in greater toxicity. However, peripheral recruitment or differentiation of CD11b+ innate phagocytic populations may be better facilitated by SRS-range doses, with the effect observed acutely within 24 h. Efforts to further understand the acute innate immune response elicited by CI are underway, and the findings could guide efforts in different models for inflammatory modulation resulting in either enhanced antitumor immunity or decreased risk of CI-induced sequelae such as radionecrosis.