The Influence of Radiotherapy on AIM2 Inflammasome in Radiation Pneumonitis
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ORIGINAL ARTICLE
The Influence of Radiotherapy on AIM2 Inflammasome in Radiation Pneumonitis Qianyu Zhang,1 Qinyong Hu,1 Yuxin Chu,1 Bin Xu,1 and Qibin Song1,2
Abstract—This study aims to investigate the influence of radiotherapy on absent in melanoma 2 (AIM2) inflammasome in radiation pneumonitis (RP). A rat model of RP was established. H&E staining was used to test radiation-induced lung tissue injury. Immunohistochemistry (IHC) was used to detect the expression of AIM2 and IL-1β in rat lung tissues. Milliplex assay was used to test cytokine levels in rat serum. Comet assay was adopted to examine DNA breaks in THP1 cells. RT-PCR was used to detect the messenger RNA (mRNA) expression of AIM2, caspase-1, and IL-1β in THP1 cells. As a result, the rat model indicated that irradiation induced obvious lung injury. A large amount of inflammatory cells infiltrated to the irradiated lung tissues. The structure of lung tissues collapsed. IHC revealed that AIM2 and IL-1β expressions were significantly higher in irradiated lung tissues than in the control. IL-1β level in rat serum significantly elevated on the 7th day post-irradiation, gradually decreased on the 15th day, and became minimal on the 30th day. Irradiation induced dsDNA break in a dose-dependent manner at 24 h after irradiation. Radiotherapy increased the mRNA expression level of AIM2 and IL-1β in a timedependent manner. In conclusion, radiotherapy triggered some critical components of AIM2 inflammasome in RP. The activation of AIM2 inflammasome by radiotherapy may contribute to the pathogenesis of RP. KEY WORDS: radiotherapy; radiation pneumonitis (RP); AIM2; inflammasome.
INTRODUCTION Radiotherapy (RT) has been regarded as a vital treatment for more than 70 % of thoracic cancers [1]. However, the lung is relatively sensitive to irradiation [2], about 13– 37 % of patients who received radical RT were susceptible to develop radiation pneumonitis (RP) [3]. The molecular mechanism of RP may involve inflammatory cytokines, such as colony-stimulating factor (G-CSF), interleukin-6 (IL-6), keratinocyte-derived chemokines (KC), genetic background, numerous specific cell types, and multiple regulatory signaling pathways [4]. However, the definitive Qianyu Zhang and Qinyong Hu contributed equally to this work. 1
Department of Oncology I, Renmin Hospital of Wuhan University, 430060 Wuhan, China 2 To whom correspondence should be addressed at Department of Oncology I, Renmin Hospital of Wuhan University, 430060 Wuhan, China. E-mail: [email protected]
mechanism of RP is still unknown. Clarifying the detailed pathology and acquiring precise mechanistic insights into RP is necessary for the investigation of pharmacological and biological therapeutics to prevent and treat this disease [4]. Inflammasome has recently been reported to involve and accelerate radiation-induced pneumonitis and fibrosis in mice [5]. The inflammasomes are a group of multimeric protein complex which is composed of an inflammasome sensor molecule, such as NLRP3, absent in melanoma 2 (AIM2), or RIG-
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