STING facilitates the development of radiation-induced lung injury via regulating the PERK/eIF2α pathway

Xiangwei Ge; Qiaowei Liu; Hao Fan; Hongyang Yu; Jinfeng Li; Yao Li; Boyu Qin; Junxun Ma; Jinliang Wang; Yi Hu

doi:10.21037/tlcr-24-649

STING facilitates the development of radiation-induced lung injury via regulating the PERK/eIF2α pathway

Transl Lung Cancer Res. 2024 Nov 30;13(11):3010-3025. doi: 10.21037/tlcr-24-649. Epub 2024 Nov 21.

Authors

Xiangwei Ge^#^{1

2}, Qiaowei Liu^#^{3

4}, Hao Fan^{1

2}, Hongyang Yu¹, Jinfeng Li³, Yao Li^{1

2}, Boyu Qin³, Junxun Ma³, Jinliang Wang³, Yi Hu²

Affiliations

¹ Medical School of Chinese PLA, Beijing, China.
² Department of Oncology, the First Medical Center, Chinese PLA General Hospital, Beijing, China.
³ Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.
⁴ Department of Emergency, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.

^# Contributed equally.

Abstract

Background: Radiation-induced lung injury (RILI) is one of the serious adverse reactions of thoracic radiotherapy, which largely limits the dose and therapeutic effect of radiotherapy. The underlying mechanism has not been elucidated. RILI is characterized by an acute inflammatory response, and stimulator of interferon genes (STING) has been reported to play an important role in regulating inflammation and innate immune activation. However, its role in RLLI, remains unclear. Here, we reported the potential therapeutic effect of STING inhibitor H-151 on RILI.

Methods: C57BL/6J mice were exposed to 20 Gy whole-thorax irradiation and H-151 was injected intraperitoneally from the day of irradiation for 4 weeks. The degree of RILI was then assessed. To further explore the mechanism of STING in RILI, the supernatant of irradiated lung epithelial cell MLE-12 was co-cultured with embryonic fibroblast cell NIH/3T3.

Results: The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway is abnormally activated in irradiated mouse lung tissues. The early application of STING inhibitor significantly alleviated radiation-induced inflammatory cell infiltration and pro-inflammatory cytokine release in lung tissue, as well as the degree of fibrosis in the late stage. The amount of double-stranded DNA (dsDNA) in the supernatant of irradiated MLE-12 cells was abnormally increased, and the epithelial-derived dsDNA could promote the transformation of fibroblasts into myofibroblasts. Mechanistically, STING could mediate the activation of fibroblasts to myofibroblasts via the PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) pathway.

Conclusions: Our study focused on the activation of cGAS-STING signaling pathway in RILI, and inhibition of STING significantly ameliorated RILI in mice. STING mediated the effect of radiation-induced dsDNA release to stimulate the activation of inflammatory response, and STING restriction significantly delayed the fibrosis process through the PERK-eIF2α pathway, suggesting that STING intervention may pave a new avenue for the treatment of RILI.

Keywords: PKR-like endoplasmic reticulum kinase (PERK); Radiation-induced lung injury (RILI); fibrosis; inflammation; stimulator of interferon genes (STING).