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Ionizing radiation selectively reduces skin regulatory T cells and alters immune function.

ABSTRACT: The skin serves multiple functions that are critical for life. The protection from pathogens is achieved by a complicated interaction between aggressive effectors and controlling functions that limit damage. Inhomogeneous radiation with limited penetration is used in certain types of therapeutics and is experienced with exposure to solar particle events outside the protection of the Earth's magnetic field. This study explores the effect of ionizing radiation on skin immune function. We demonstrate that radiation, both homogeneous and inhomogeneous, induces inflammation with resultant specific loss of regulatory T cells from the skin. This results in a hyper-responsive state with increased delayed type hypersensitivity in vivo and CD4+ T cell proliferation in vitro. The effects of inhomogeneous radiation to the skin of astronauts or as part of a therapeutic approach could result in an unexpected enhancement in skin immune function. The effects of this need to be considered in the design of radiation therapy protocols and in the development of countermeasures for extended space travel.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC4069168 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Ionizing radiation selectively reduces skin regulatory T cells and alters immune function.

Zhou Yu Y Ni Houping H Balint Klara K Sanzari Jenine K JK Dentchev Tzvete T Diffenderfer Eric S ES Wilson Jolaine M JM Cengel Keith A KA Weissman Drew D

PloS one 20140624 6

The skin serves multiple functions that are critical for life. The protection from pathogens is achieved by a complicated interaction between aggressive effectors and controlling functions that limit damage. Inhomogeneous radiation with limited penetration is used in certain types of therapeutics and is experienced with exposure to solar particle events outside the protection of the Earth's magnetic field. This study explores the effect of ionizing radiation on skin immune function. We demonstra ...[more]

PMID: 24959865

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Project description:BackgroundRadiation-induced skin injury (RISI) is still the most common and severe side effect of radiotherapy. The role of the skin's microbial barrier in the pathogenesis and progression of RISI needs to be fully investigated.MethodsThis study aimed to explore the alterations in and functions of the skin microbiota in RISI. We applied the unculturable approach to characterize the cutaneous microbiomes of a radiation-induced animal model by sequencing the V1-V3 regions of the 16S ribosomal RNA (rRNA) gene. Combined with the downloaded clinical data of patients, a comprehensive analysis was performed to identify potential radioprotective species and metabolic pathways.ResultsThere were no significant differences in the alpha diversity indices (Sobs, Shannon, Simpson, Ace, and Chao) between the acute radiation injury and control groups. Phylum-level analysis of the RISI microbiomes exhibited significant predominance of Firmicutes (mean abundance = 67%, corrected p = 0.0035). The high abundance of Firmicutes was significantly associated with rapid healing of RISI (average relative abundance = 52%; Kruskal-Wallis: p = 5.7E-4). Among its members, Streptococcus, Staphylococcus, Acetivibrio ethanolgignens group, Peptostreptococcus, Anaerofilum, and UCG-002 [linear discriminant analysis (LDA) > 3, p < 0.05] were identified as the core genera of Firmicutes. In addition, Lachnosiraceae and Lactobacillus occupied an important position in the interaction network (r > 0.6, p < 0.05). The differential metabolic pathways of RISI were mainly associated with carbohydrate metabolism (butanoate and propanoate metabolism), amino acid metabolism (tryptophan and histidine metabolism), energy metabolism, and lipid metabolism (fatty acid degradation and biosynthesis).ConclusionThis study provides new insights into the potential mechanism and skin microbial changes in the progression of RISI. The overwhelming predominance of members of Firmicutes, including Streptococcaceae, Staphylococcaceae, Lachnospiraceae, and Lactobacillus, is potentially related to rapid healing of RISI. The microbiota-metabolite axis plays a critical role in RISI and provides promising therapeutic targets for the treatment of adverse side effects.

Project description:BackgroundMost cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients' quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model.MethodsAthymic mice were treated intraperitoneally with saline or Vasculotide and their flank skin was irradiated with a single large dose of ionizing radiation. Acute cutaneous damage and wound healing were evaluated by clinical skin grading, histology and immunostaining. Diffuse reflectance optical spectroscopy, myeloperoxidase-dependent bioluminescence imaging of neutrophils and a serum cytokine array were used to assess inflammation. Microvascular endothelial cell response to radiation was tested with in vitro clonogenic and Matrigel tubule formation assays. Tumour xenograft growth delay experiments were also performed. Appreciable differences between treatment groups were assessed mainly using parametric and non-parametric statistical tests comparing areas under curves, followed by post-hoc comparisons.ResultsIn vivo, different schedules of Vasculotide treatment reduced the size of the irradiation-induced wound. Although skin damage scores remained similar on individual days, Vasculotide administered post irradiation resulted in less skin damage overall. Vasculotide alleviated irradiation-induced inflammation in the form of reduced levels of oxygenated hemoglobin, myeloperoxidase bioluminescence and chemokine MIP-2. Surprisingly, Vasculotide-treated animals also had higher microvascular endothelial cell density in wound granulation tissue. In vitro, Vasculotide enhanced the survival and function of irradiated endothelial cells.ConclusionsVasculotide administration reduces acute skin radiation damage in mice, and may do so by affecting several biological processes. This radiation protection approach may have clinical impact for cancer radiotherapy patients by reducing the severity of their acute skin radiation damage.

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Ionizing radiation selectively reduces skin regulatory T cells and alters immune function.

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Ionizing radiation selectively reduces skin regulatory T cells and alters immune function.

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