Inhibition of AIM2 inflammasome-mediated pyroptosis by Andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis

Jian Gao,Jian Sun,Zhigang Chang,Lihong Shen,Lingdong Kong,Xiaoling Yang,Chunhong Jiang,Xinni Shan,Shuang Peng,Fude Feng,Wenjie Guo,Qiang Xu,Yang Sun,Guoliang Deng,Yanhong Gu,Xinchen Sun

doi:10.1038/s41419-019-2195-8

Abstract

Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate, is prescribed as a treatment for upper respiratory tract infection. Here we report the potential radioprotective effect and mechanism of Andrographolide on RILI. C57BL/6 mice were exposed to 18 Gy of whole thorax irradiation, followed by intraperitoneal injection of Andrographolide every other day for 4 weeks. Andrographolide significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release in the early phase and progressive fibrosis in the late phase. Moreover, Andrographolide markedly hampered radiation-induced activation of the AIM2 inflammasome and pyroptosis in vivo. Furthermore, bone marrow-derived macrophages (BMDMs) were exposed to 8 Gy of X-ray radiation in vitro and Andrographolide significantly inhibited AIM2 inflammasome mediated-pyroptosis in BMDMs. Mechanistically, Andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation or chemotherapeutic agents in BMDMs. Taken together, Andrographolide ameliorates RILI by suppressing AIM2 inflammasome mediated-pyroptosis in macrophage, identifying Andrographolide as a novel potential protective agent for RILI.

Highlights

Radiotherapy is an important therapeutic modality for a variety of tumors such as lung cancer, breast cancer, prostate cancer, and renal cell carcinoma[1,2,3,4]
Using primary cultured bone marrow-derived macrophage (BMDM) radiation model, we revealed that Andrographolide markedly hampered the activation of the AIM2 inflammasome and pyroptosis in macrophages by preventing AIM2 from translocating into the nucleus to sense DNA damage induced by radiation
Andrographolide protected mice from lung injury induced by thoracic radiotherapy We designed a mouse model of Radiation-induced lung injury (RILI) in which mice were exposed to 18 Gy of whole-thorax irradiation

Summary

Introduction

Radiotherapy is an important therapeutic modality for a variety of tumors such as lung cancer, breast cancer, prostate cancer, and renal cell carcinoma[1,2,3,4]. Accumulating evidence suggests that AIM2 inflammasome-mediated pyroptosis both in macrophages and epithelial cells plays a critical role in the development of radiation-induced tissue injury[9,10]. Pyroptosis, recognized as a form of cell death distinct from apoptosis, is caused by activation of inflammasomes[11]. The AIM2 inflammasome, comprised of AIM2 and ASC, recognizes double-stranded DNA breaks (DSBs) caused by ionizing radiation and chemotherapeutic agents[12,13]. AIM2 translocates into the nucleus and localizes at the foci of DSB, forming specks and recruits ASC, which leads to Caspase-1 activation. Activated Caspase-1 causes the enzymolysis of the inflammatory cytokines interleukin (IL)-1β and IL-18 or the cleavage of Gasdermin D, which induces pore formation on the plasma membrane, resulting in cell swelling and the release of cytosolic contents such as lactate dehydrogenase (LDH) and pro-inflammatory cytokines[14,15,16,17,18]

Methods

Results

Conclusion