Autophagy Induced by Micheliolide Alleviates Acute Irradiation-Induced Intestinal Injury via Inhibition of the NLRP3 Inflammasome.

Dong-Ming Wu,Ying Xu,Jing Li,Rong Shen,Li Li,Ting Zhang,Teng Liu,De-Gui Wang,Shi-Hua Deng,Jin Li,Ye Yu

doi:10.3389/fphar.2021.773150

Abstract

Radiation-induced enteropathy (RIE) is one of the most common and fatal complications of abdominal radiotherapy, with no effective interventions available. Pyroptosis, a form of proinflammatory regulated cell death, was recently found to play a vital role in radiation-induced inflammation and may represent a novel therapeutic target for RIE. To investigate this, we found that micheliolide (MCL) exerted anti-radiation effects in vitro. Therefore, we investigated both the therapeutic effects of MCL in RIE and the possible mechanisms by which it may be therapeutic. We developed a mouse model of RIE by exposing C57BL/6J mice to abdominal irradiation. MCL treatment significantly ameliorated radiation-induced intestinal tissue damage, inflammatory cell infiltration, and proinflammatory cytokine release. In agreement with these observations, the beneficial effects of MCL treatment in RIE were abolished in Becn1 +/− mice. Furthermore, super-resolution microscopy revealed a close association between NLR pyrin domain three and lysosome-associated membrane protein/light chain 3-positive vesicles following MCL treatment, suggesting that MCL facilitates phagocytosis of the NLR pyrin domain three inflammasome. In summary, MCL-mediated induction of autophagy can ameliorate RIE by NLR pyrin domain three inflammasome degradation and identify MCL as a novel therapy for RIE.

Highlights

Radiotherapy is an important treatment strategy for several malignancies including lung cancer, prostate cancer, and renal cell carcinoma
We observed that cell viability was significantly decreased in a dose-dependent manner following treatment with radiation for 24, 48, or 72 h (Figure 1A, and lactate dehydrogenase (LDH) release increased in a time-and dose-dependent manner (Figure 1B)
To determine whether autophagy is involved in the degradation of the NLRP3 inflammasome, we evaluated the co-localization of NLRP3 with light chain 3 (LC3) and lysosome-associated membrane protein (LAMP-1)

Summary

Introduction

Radiotherapy is an important treatment strategy for several malignancies including lung cancer, prostate cancer, and renal cell carcinoma. RIE remains the most common and severe complication of the treatment of abdominal malignancies (Nussbaum et al, 1993; Lu et al, 2019). The well-known symptoms of RIE, including gastrointestinal hemorrhage, endotoxemia, bacterial infection, anorexia, Micheliolide Alleviates Intestinal Injury nausea, vomiting, diarrhea, and loss of electrolytes and fluid, limit the therapeutic potential of radiotherapy in patients with abdominal malignancies and prevent further use of fractionated radiotherapy (Shadad et al, 2013; Hauer-Jensen et al, 2014). Patients with RIE appear nausea and vomiting, abdominal pain and diarrhea, tenesmus and other clinical symptoms, significantly reduce the life quality of patients, even cause serious complications such as colon stenosis, intestinal fibrosis and aggravate patients, greatly restricts the implementation of radiotherapy for patients with malignant tumors (Takemura et al, 2018; Akahane et al, 2020).

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