Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury

Cellular & Molecular Immunology volume 18, pages 1718–1728 (2021)Cite this article

Subjects

Abstract

Liver damage upon exposure to ionizing radiation (IR), whether accidental or therapeutic, can contribute to liver dysfunction. Currently, radiotherapy (RT) is used for various cancers including hepatocellular carcinoma (HCC); however, the treatment dose is limited by radiation-induced liver disease (RILD) with a high mortality rate. Furthermore, the precise molecular mechanisms of RILD remain poorly understood. Here, we investigated RILD pathogenesis using various knockout mouse strains subjected to whole-liver irradiation. We found that hepatocytes released a large quantity of double-stranded DNA (dsDNA) after irradiation. The cGAS-STING pathway in non-parenchymal cells (NPCs) was promptly activated by this dsDNA, causing interferon (IFN)-I production and release and concomitant hepatocyte damage. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against RILD. Moreover, clinically irradiated human peri-HCC liver tissues exhibited substantially higher STING and IFNβ expression than non-irradiated tissues. Increased serum IFNβ concentrations post-radiation were associated with RILD development in patients. These results delineate cGAS-STING induced type 1 interferon release in NPCs as a key mediator of IR-induced liver damage and described a mechanism of innate-immunity-driven pathology, linking cGAS-STING activation with amplification of initial radiation-induced liver injury.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90. (2011).

    Article  PubMed  Google Scholar 

  2. Karaman, B., Battal, B., Sari, S. & Verim, S. Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J. Gastroenterol. 20, 18059–18060 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gerum, S., Jensen, A. D. & Roeder, F. Stereotactic body radiation therapy in patients with hepatocellular carcinoma: a mini-review. World J. Gastrointest. Oncol. 11, 367–376 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Koay, E. J., Owen, D. & Das, P. Radiation-induced liver disease and modern radiotherapy. Semin. Radiat. Oncol. 28, 321–331 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dawson, L. A. et al. Analysis of radiation-induced liver disease using the Lyman NTCP model. Int. J. Radiat. Oncol. Biol. Phys. 53, 810–821 (2002).

    Article  PubMed  Google Scholar 

  6. Wang, S. et al. Liver toxicity induced by combined external-beam irradiation and radioimmunoglobulin therapy. Radiat. Res. 141, 294–302 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Du, S. S. et al. Inactivation of kupffer cells by gadolinium chloride protects murine liver from radiation-induced apoptosis. Int. J. Radiat. Oncol. Biol. Phys. 76, 1225–1234 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Christiansen, H. et al. Irradiation leads to susceptibility of hepatocytes to TNF-alpha mediated apoptosis. Radiother. Oncol. 72, 291–296 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Dong, Y. et al. Activation of the JNK-c-Jun pathway in response to irradiation facilitates Fas ligand secretion in hepatoma cells and increases hepatocyte injury. J. Exp. Clin. Cancer Res. 35, 114 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gao, D. et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc. Natl. Acad. Sci. USA 112, E5699–E5705 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gray, E. E., Treuting, P. M., Woodward, J. J. & Stetson, D. B. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of aicardi-goutieres syndrome. J. Immunol. 195, 1939–1943 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Demaria, O. et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl. Acad. Sci. USA 112, 15408–15413 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, M. J., Chen, F., Lau, J. T. Y. & Hu, Y. P. Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis. 8, e2805 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Petrasek, J. et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc. Natl. Acad. Sci. USA 110, 16544–16549 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ahn, J., Gutman, D., Saijo, S. & Barber, G. N. STING manifests self DNA-dependent inflammatory disease. Proc. Natl. Acad. Sci. USA 109, 19386–19391 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lawrence, T. S. et al. Hepatic toxicity resulting from cancer treatment. Int. J. Radiat. Oncol. Biol. Phys. 31, 1237–1248 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Araujo A. M., et al. Liver immune cells release type 1 interferon due to DNA sensing and amplify liver injury from acetaminophen overdose. Cells 7, 1–16. https://doi.org/10.3390/cells7080088 (2018).

  24. Thomsen, M. K. et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatology 64, 746–759 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Barber, G. N. STING: infection, inflammation and cancer. Nat. Rev. Immunol. 15, 760–770 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bhattacharya, A. et al. Superoxide dismutase 1 protects hepatocytes from type I interferon-driven oxidative damage. Immunity 43, 974–986 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mapuskar, K. A., Anderson, C. M., Spitz, D. R., Batinic-Haberle, I. & Allen, B. G. Utilizing superoxide dismutase mimetics to enhance radiation therapy response while protecting normal tissues. Semin. Radiat. Oncol. 29, 72–80 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nagata, S. Apoptosis and autoimmune diseases. Ann. N. Y. Acad. Sci. 1209, 10–16 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Munoz-Schuffenegger, P., Ng, S. & Dawson, L. A. Radiation-induced liver toxicity. Semin. Radiat. Oncol. 27, 350–357 (2017).

    Article  PubMed  Google Scholar 

  30. Deng, Z. B. et al. Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 50, 1412–1420 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Xu, H. et al. Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance. J. Biol. Chem. 289, 16374–16388 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Iracheta-Vellve, A. et al. Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. J. Biol. Chem. 291, 26794–26805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Qiao, J. T. et al. Activation of the STING-IRF3 pathway promotes hepatocyte inflammation, apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease. Metabolism 81, 13–24 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Cho, C. S. et al. Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation. Hepatology 68, 1331–1346 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Malhi, H. & Gores, G. J. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 28, 360–369 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tosello-Trampont, A. C., Landes, S. G., Nguyen, V., Novobrantseva, T. I. & Hahn, Y. S. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J. Biol. Chem. 287, 40161–40172 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alati, T., Van Cleeff, M., Strom, S. C. & Jirtle, R. L. Radiation sensitivity of adult human parenchymal hepatocytes. Radiat. Res. 115, 152–160 (1988).

    Article  CAS  PubMed  Google Scholar 

  38. Radoshevich, L. & Dussurget, O. Cytosolic innate immune sensing and signaling upon infection. Front. Microbiol. 7, 313 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554.e12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Katlinski, K. V. et al. Inactivation of interferon receptor promotes the establishment of immune privileged tumor microenvironment. Cancer Cell 31, 194–207 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Woo, S.-R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Spranger, S. et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 5, 200ra116 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Weichselbaum, R. R. et al. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc. Natl. Acad. Sci. USA 105, 18490–18495 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Boelens, M. C. et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, 499–513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Erdal, E., Haider, S., Rehwinkel, J., Harris, A. L. & McHugh, P. J. A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1. Genes Dev. 31, 353–369 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Post, A. E. M. et al. Interferon-stimulated genes are involved in cross-resistance to radiotherapy in tamoxifen-resistant breast cancer. Clin. Cancer Res. 24, 3397–3408 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Chen, J. et al. IFN protects cancer cells from CD8+ T cell-mediated cytotoxicity after radiation. J. Clin. Invest. 129, 4224–4238 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Xu, H. et al. ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery. Blood 130, 11–22 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Wu, Z. F. et al. Toll-like receptor 4 and its associated proteins as prognostic factors for HCC treated by post-radiotherapy surgery. Oncol. Lett. 15, 9599–9608 (2018).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Nature Science Foundation of China (No. 81773220 and U1505229).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Shisuo Du, Genwen Chen, Baoying Yuan, Yong Hu, Ping Yang, Yixing Chen, Qianqian Zhao & Zhaochong Zeng

  2. Liver Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jian Zhou & Jia Fan

Authors
  1. Shisuo Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Genwen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baoying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yixing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qianqian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jian Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhaochong Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study concept and design: S.D. and Z.Z.; acquisition of data: G.C. and S.D.; analysis and interpretation of data: S.D. and G.C.; acquisition of patient specimens: P.Y., Y.C., Y.H. and S.D.; drafting of the manuscript: S.D. and Z.Z.; critical revision of the manuscript: J.Z., J.F. and Z.Z.; obtained funding: administrative, Z.Z.; technical or other material support: S.D. and G.C.; study supervision: Z.Z.

Corresponding author

Correspondence to Zhaochong Zeng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, S., Chen, G., Yuan, B. et al. DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury. Cell Mol Immunol 18, 1718–1728 (2021). https://doi.org/10.1038/s41423-020-0395-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-0395-x

Keywords

This article is cited by

Search

Advanced search

Quick links