Suppression of radiation-induced DNA double-strand break repair by MyD88 is accompanied by apoptosis and crypt loss in mouse colon

Abstract

Intestinal microbes promote the injurious effects of radiation on those tissues. However, the molecular factors mediating this effect are largely unknown. In this work, we explored the effects of orally administered antibiotics and MyD88, a key adapter molecule in toll-like receptor signaling, on molecular and cellular responses of mouse colon to radiation. Results show that oral antibiotics lowered radiation-induced colonic damage by protecting epithelial cells against radiation-induced apoptosis, leading to increased survival of crypts. MyD88 deficiency partially phenocopied the effects of oral antibiotics on apoptosis and crypt survival, suggesting that colonic microbes exert their injurious effects in part via that molecule. Analysis of DNA double-strand breaks, the primary genotoxic lesions induced by radiation, showed that their early induction in mouse colon was unaffected by MyD88. However, MyD88 deficiency resulted in the later disappearance of DNA double-strand breaks. Loss of DNA double-strand breaks was accompanied by the evidence of increased activation of both the non-homologous end-joining and homologous recombination pathways of DNA repair in MyD88-deficient mice. These results show that colonic microbes and MyD88 regulate DNA double-strand break repair in irradiated mouse colon, effects which exert significant control over radiation-induced apoptosis and crypt survival.

Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome

“…In the present study, we investigated the radiation susceptibilities of TLR-knockout mice to evaluate the impact of TLR deficiency on GIS. A recent study has suggested that Myd88 − / − mice showed marked resistance to GIS35. However, our study revealed that there was no attenuation of GIS in mice deficient in TLR2, 4, 5, 7 and 9.…”

Sam68/KHDRBS1-dependent NF-κB activation confers radioprotection to the colon epithelium in γ-irradiated mice

“…Tissue sections (5-micron) were cut, deparaffinised, rehydrated, and stained with hematoxylin and Eosin (H and E) staining and stained sections were washed and mounted under a coverslip and examined under light microscopy (Zeiss). The crypt survival assays (Lai and Egan, 2013) were employed to evaluate the radio-sensitivity of the colon post whole-body γ-irradiation in mice.…”

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

“…The interaction of TLR4, and its co‐receptors CD14 and MD‐2, with LPS results in recruitment of the adapter molecule myeloid differentiation marker 88 (MyD88), phosphorylation of IL‐1 receptor associated kinase and recruitment of the adapter molecule tumor necrosis factor receptor‐associated factor (TRAF)−6 . Recent research has attempted to delineate the mechanisms by which TLR4 contributes to gastrointestinal immunity by altering intestinal microbes and MyD88 expression . Using a preclinical model, Lai et al .…”

“…[108][109][110] Recent research has attempted to delineate the mechanisms by which TLR4 contributes to gastrointestinal immunity by altering intestinal microbes and MyD88 expression. 111 Using a preclinical model, Lai et al administered a broad-spectrum oral antibiotic to animals treated with 14Gy of whole body irradiation. Antibiotic administration attenuated weight loss, and increased food and water intake.…”