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Interleukin 6 Signaling Blockade Exacerbates Acute and Late Injury From Focal Intestinal Irradiation.

ABSTRACT: PURPOSE:To evaluate the acute changes in leukocyte populations after focal irradiation and to assess the role of interleukin 6 (IL-6) in acute and late radiation injury. METHODS AND MATERIALS:Mice were surgically implanted with a radiopaque marker on the surface of the small intestine. Mice were then imaged with cone beam computed tomography to locate the marker and irradiated with 18 Gy of 5 × 5 mm collimated x-rays onto the marked intestine using the Small Animal Radiation Research Platform. Intestinal sections and blood were harvested 1, 3.5, 7, and 14 days and 2 months postirradiation (post-IR) for histology and complete blood count, respectively. Immune cell populations were assessed by immunofluorescence in the acute phase. Collagen deposition was assessed 2 months post-IR. IL-6^-/- intestinal sections were assessed post-IR for morphology, EdU, Ki67, and TUNEL in comparison to IL-6^+/+ mice. Furthermore, a set of IL-6^+/+ mice were treated with anti-IL-6R to assess the role of IL-6 in late intestinal injury. RESULTS:Intestinal radiation damage peaked 14 days post-IR, and fibrosis had developed by 60 days post-IR. There was a marked infiltration of immune cells into the irradiated intestine, with increased neutrophils, macrophages, B-cells, and CD4⁺ T cells maintained from 3.5 to 14 days post-IR. CD8⁺ T cells were decreased from days 7 to 14 post-IR. Systemically, leukocytes were increased in the peripheral blood 14 days post-IR with anemia being maintained from 14 days to 2 months. IL-6 was significantly increased in the serum post-IR. IL-6^-/- mice demonstrated worsened intestinal injury acutely post-IR. Moreover, anti-IL-6R-treated mice presented with worsened intestinal fibrosis 2 months post-IR. CONCLUSIONS:Focal irradiation of the intestine produced a significant increase in immune cells in the irradiated area and systemic inflammation and anemia. Blockade of IL-6 signaling was found to exacerbate acute intestinal injury and late intestinal injury after focal irradiation.

SUBMITTER: Bell BI

PROVIDER: S-EPMC7699458 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Interleukin 6 Signaling Blockade Exacerbates Acute and Late Injury From Focal Intestinal Irradiation.

Bell Brett I BI Koduri Sravya S Salas Salinas Carlo C Monslow James J Puré Ellen E Ben-Josef Edgar E Koumenis Constantinos C Verginadis Ioannis I II

International journal of radiation oncology, biology, physics 20181015 3

<h4>Purpose</h4>To evaluate the acute changes in leukocyte populations after focal irradiation and to assess the role of interleukin 6 (IL-6) in acute and late radiation injury.<h4>Methods and materials</h4>Mice were surgically implanted with a radiopaque marker on the surface of the small intestine. Mice were then imaged with cone beam computed tomography to locate the marker and irradiated with 18 Gy of 5 × 5 mm collimated x-rays onto the marked intestine using the Small Animal Radiation Resea ...[more]

PMID: 30336264

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Project description:Background: Inflammatory bowel disease (IBD) involves complicated crosstalk between host immunity and the gut microbiome, whereas the mechanics of how they govern intestinal inflammation remain poorly understood. In this study, we investigated the contribution of environmental factors to shaping gut microbiota composition in colitis mice that were transgenic for human IL-37, a natural anti-inflammatory cytokine possessing pathogenic and protective functions related to microbiota alterations. Methods: Mice transgenic expressing human IL-37 (IL-37tg) were housed under conventional and specific pathogen-free (SPF) conditions to develop a mouse model of dextran sulfate sodium (DSS)-induced colitis. 16S ribosomal RNA sequencing was used for analyzing fecal microbial communities. The efficacy of microbiota in the development of colitis in IL-37tg mice was investigated after antibiotic treatment and fecal microbiota transplantation (FMT). The mechanism by which IL-37 worsened colitis was studied by evaluating intestinal epithelial barrier function, immune cell infiltration, the expression of diverse cytokines and chemokines, as well as activated signaling pathways. Results: We found that IL-37 overexpression aggravated DSS-induced colitis in conventional mice but protected against colitis in SPF mice. These conflicting results from IL-37tg colitis mice are ascribed to a dysbiosis of the gut microbiota in which detrimental bacteria increased in IL-37tg conventional mice. We further identified that the outcome of IL-37-caused colon inflammation is strongly related to intestinal epithelial barrier impairment caused by pathogenic bacteria, neutrophils, and NK cells recruitment in colon lamina propria and mesenteric lymph node to enhance inflammatory responses in IL-37tg conventional mice. Conclusions: The immunoregulatory properties of IL-37 are detrimental in the face of dysbiosis of the intestinal microbiota, which contributes to exacerbated IBD occurrences that are uncontrollable by the immune system, suggesting that depleting gut pathogenic bacteria or maintaining intestinal microbial and immune homeostasis could be a promising therapeutic strategy for IBD.

Dataset Information

Interleukin 6 Signaling Blockade Exacerbates Acute and Late Injury From Focal Intestinal Irradiation.

Publications

Interleukin 6 Signaling Blockade Exacerbates Acute and Late Injury From Focal Intestinal Irradiation.

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