Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
Institute of Biophysics, Chinese Academy of Sciences. Beijing, China.
Sci Immunol. 2021 May 7;6(59). doi: 10.1126/sciimmunol.abc6998.
The inflammasome promotes inflammation-associated diseases, including cancer, and contributes to the radiation-induced tissue damage. However, the role of inflammasome in radiation-induced antitumor effects is unclear. We observed that tumors transplanted in mice were resistant to radiation treatment compared with tumors in wild-type (WT) mice. To map out which molecule in the inflammasome pathway contributed to this resistant, we investigated the antitumor effect of radiation in several inflammasome-deficient mice. Tumors grown in either or mice remained sensitive to radiation, like WT mice, whereas mice showed radioresistance. Mechanistically, extracellular vesicles (EVs) and EV-free supernatant derived from irradiated tumors activated both Aim2 and Nlrp3 inflammasomes in macrophages, leading to the production of interleukin-1β (IL-1β). IL-1β treatment helped overcome the radioresistance of tumors growing in and mice. IL-1 signaling in dendritic cells (DCs) promoted radiation-induced antitumor immunity by enhancing the cross-priming activity of DCs. Overall, we demonstrated that radiation-induced activation of the AIM2 and NLRP3 inflammasomes coordinate to induce some of the antitumor effects of radiation by triggering IL-1 signaling in DCs, leading to their activation and cross-priming.
炎症小体促进炎症相关疾病，包括癌症，并导致辐射诱导的组织损伤。然而，炎症小体在辐射诱导的抗肿瘤作用中的作用尚不清楚。我们观察到，与野生型（WT）小鼠相比，移植到 小鼠中的肿瘤对放射治疗具有抗性。为了阐明炎症小体途径中的哪个分子导致这种抗性，我们研究了几种炎症小体缺陷型小鼠中辐射的抗肿瘤作用。在 或 小鼠中生长的肿瘤仍然对辐射敏感，与 WT 小鼠一样，而 小鼠则表现出辐射抗性。从机制上讲，来自辐照肿瘤的细胞外囊泡（EVs）和 EV 无上清液激活了巨噬细胞中的 Aim2 和 Nlrp3 炎症小体，导致白细胞介素-1β（IL-1β）的产生。IL-1β 处理有助于克服在 和 小鼠中生长的肿瘤的放射抗性。DC 中的 IL-1 信号转导通过增强 DC 的交叉呈递活性促进了辐射诱导的抗肿瘤免疫。总之，我们证明了辐射诱导的 AIM2 和 NLRP3 炎症小体的激活通过触发 DC 中的 IL-1 信号转导来协调诱导辐射的一些抗肿瘤作用，从而导致其激活和交叉呈递。
