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Exosomes are involved in total body irradiation-induced intestinal injury in mice

Abstract

Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg−1·d−1, ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.

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Fig. 1: Exo-IR-24h decreases the survival rate of mice after TBI.
Fig. 2: Exo-IR-24h enhances TBI-induced small intestinal damage in mice.
Fig. 3: Exo-IR-24h attenuates ISC survival and abolishes the regeneration of intestinal cells after TBI.
Fig. 4: Exo-IR-24h promotes apoptosis and DNA damage in the small intestines of mice exposed to TBI.
Fig. 5: Exo-IR-24h suppresses cell proliferation and enhances oxidative DNA damage in irradiated MODE-K cells.
Fig. 6: Exo-IR-24h promotes IR-induced DNA damage and apoptosis by attenuating the Nrf2-mediated antioxidant response in MODE-K cells.
Fig. 7: Total body irradiation modulates the expression levels of exosomal miRNAs in mice.
Fig. 8: The GO biological processes and KEGG pathways significantly enriched with putative genes targeted by the exosomal microRNAs.
Fig. 9: Total body irradiation induces intestinal injury through serum exosomal miRNAs in mice.
Fig. 10: Exosomes are involved in total body irradiation-induced intestinal injury in mice.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81803046 and No. 81730086), the Natural Science Foundation of Tianjin City (19JCQNJC09700), and the CAMS Innovation Fund for Medical Sciences (2017-I2M-B&R-13).

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HL and SJF conceived the project idea and designed the experiments. HL, MJ, SYZ and SQZ performed the experiments. LL and GXF performed data analysis. XH and XW assisted in data interpretation and manuscript revision. HL drafted the article and wrote the entire manuscript. All authors commented on and approved the manuscript.

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Correspondence to Hang Li or Sai-jun Fan.

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Li, H., Jiang, M., Zhao, Sy. et al. Exosomes are involved in total body irradiation-induced intestinal injury in mice. Acta Pharmacol Sin 42, 1111–1123 (2021). https://doi.org/10.1038/s41401-021-00615-6

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Keywords

  • total body irradiation
  • radiation-induced intestinal injury
  • DNA damage
  • apoptosis
  • exosome
  • MicroRNA
  • GW4869

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