Activation of NLRP3 inflammasome in lung epithelial cells triggers radiation-induced lung injury

Abstract

Background Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. Methods RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1β on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines. Results NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1β secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. Conclusions Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.

Identification of Itgb1 as a critical gene for radiation-induced injury by bioinformatic analysis combined with experimental verification

“…To date, efforts to develop targeted drugs for sites of ionizing radiation damage, such as NLRP3 in ammasome [32,33], have yielded little bene t and therapeutic options for clinical treatment have not been studied in detail [34]. However, none of these treatment options has been studied in detail.…”

Pyroptotic cell death: an emerging therapeutic opportunity for radiotherapy

“…γ radiation not only activates the NLRP1 and NLRP3 complexes in microvascular endothelial cells but also activates caspase-1 directly [ 23 ]. In lung epithelial cells, radiation-induced NLRP3 activation depends on glycolysis-associated reactive oxygen species (ROS) accumulation [ 24 ]. In addition, ROS involvement in radiation-induced NLRP3 activation has also been found in other cells [ 25 ], and irradiation-induced NLRP3 activation enhances lung hypersensitivity with more monocyte’s infiltration [ 25 ].…”

Tolerogenic dendritic cells in radiation-induced lung injury

“…Of note, damaged alveolar epithelial cells and vascular endothelial cells also secrete various cytokines, including tumor necrosis factors (TNF-α) involved in local injury and inflammatory response, transforming growth factor β-1 (TGF-β1) that promotes tissue repair and organ fibrosis, platelet-derived growth factor (PDGF), interleukins (IL-1β, IL-6, IL-8, IL-10), and monocyte chemotactic peptides ( 32 , 44 , 45 ). Among them, some studies have shown that TGF-β1-based CRISPR/Cas9 gene therapy improves lung tissue pathological damage, reduces the secretion and expression of inflammatory factors, and ultimately inhibits the progression of radiation fibrosis ( 46 ).…”