Gamma Radiation Induce Inflammasome Signaling and Pyroptosis in Microvascular Endothelial Cells

Abstract

Introduction:The extend to the clinical benefit of radiation therapy is the inability to eliminate only cancer cells and destroy normal cells such as microvascular endothelial in the vascular niche and turn induced-inflammasome signaling and cell death. These unfortunate injuries generated by ionizing radiation alter the therapeutic window and result in the reoccurrence of the malignancy. Therefore, we engaged in vitro studies by demonstrating radiation-induced inflammasome and cell death in endothelial cells. Methods: The microvascular endothelial cells were cultured in a sterile dish, then kept in a humidifier of 5% at 37°C for 12 hours/more to attain confluence, and exposed at a dose of 1.8Gy/min achieve the coveted amounts except for the control. The cells were harvested 24 hours post-irradiation. Results: Our findings indicate that gamma radiation activates the NOD-like receptor (NLR) family of NLRP1 and NLRP3 complex in microvascular endothelial cells. These complexes activate the inactive precursor of caspase-1, which cleaved to bioactive caspase −1 and enhances the production of pro-inflammatory cytokines of interleukin-1β and interleukin-18 that induce the dependent pyroptotic, which results in the production of chemokines, tumor necrosis factor-alpha (TNF-α), and high-mobility group protein-1 (HMGB-1). We also discovered the radiation could directly prompt caspase −1, which auto-cleaved to activate gasdermin D to potentiate pyroptosis independently. Discussion: Overall, these findings suggested that reducing the unfavorable effect of radiation injuries could be challenging since gamma radiation induces the microvascular endothelial cells to cell death and activates the inflammasome signaling via different pathways.

P53 transcribes GSDMD to induce delayed pyroptosis in radiation-induced intestinal injury

“…However, there is a lack of study on its role in radiation-induced intestinal injury. Although some studies had suggested the involvement of pyroptosis in radiation damage of cells [10,11], the properties speci c to radiation is not highlighted and the role of GSDMD is not clear. To ll this gap, we respectively explored the in vivo effect of GSDMD knock-out on the survival and intestinal function in mice, and its in vitro effect on radiation sensitivity of intestinal epithelial cells.…”

“…Current studies have revealed the association between pyroptosis and radiation-induced injury, yet the speci c function of GSDMD remains elusive [10,11]. In the present study, we established GSDMD knockout mouse to deeply research into the role of GSDMD and pyroptosis in RIII.…”

Hunting down NLRP3 inflammasome: An executioner of radiation-induced injury

“…Moreover, the epithelial tissues, such as oral mucosa, gut mucosa, as well as lung epithelium, are particularly susceptible to ionizing radiation. Inflammasome activation and pyroptosis have been observed in these tissues after exposure to radiation ( 47 , 48 , 53 , 69 ). Excessive cell death in epithelium may lead to the breakdown of barriers such as skin, gut mucosal barrier, and alveolar epithelial barrier.…”

“…LPS from Gram-negative bacteria may also contribute to the inflammasome cascade through non-canonical NLRP3 inflammasome activation, thereby leading to even deteriorated conditions ( 29 ). Equally important, immoderate cell death in vascular endothelial cells causes vascular dysfunction, leading to increased permeability, impaired vascular tone, and altered blood homeostasis, aggravating already severe damage caused by radiation ( 10 , 53 ).…”

APE1 promotes radiation resistance against radiation-induced pyroptosis by inhibiting the STING pathway in lung adenocarcinoma

“…The small molecule inhibitor of Mammalian apurinic/apyrimidinic (AP) endonuclease 1(APE1) can induce pyroptosis in NSCLC cells [10]. APE1, also known as APEX1, is a multifunctional enzyme involved in the BER pathway and in transcriptional regulation [11].…”