NLRP3 deletion inhibits inflammation-driven mouse lung tumorigenesis induced by benzo(a)pyrene and lipopolysaccharide

Abstract

BackgroundInflammatory micro-environment has been proposed to play a critical role in lung tumorigenesis. NLRP3 is known as an intracellular receptor involving inflammation and has been reported which is increasingly associated with tumor development, but the role in inflammation-driven lung cancer has not been fully clarified. In this study, we investigated whether lipopolysaccharide (LPS)-induced pulmonary inflammation could contribute to lung tumorigenesis induced by benzo(a)pyrene [B(a)p] in C57BL/6J mice and the role of NLRP3 in the pathogenesis.MethodsNLRP3−/− mice and C57BL/6J mice (wide-type, WT) were instilled intratracheally with B(a)p (1 mg/mouse) once a week for 4 times [the week of the last time of B(a)p treatment named Week 0], and mice were then instilled intratracheally with LPS at Week 3, 2.5 μg/mouse, once every three weeks for 5 times. At Week 30, the incidence, number, size and histopathology of lung tumor were analyzed.ResultsMice exposed to B(a)p or B(a)p plus LPS could induce lung tumors, whereas LPS or vehicles treatment could not induce lung tumorigenesis. In WT mice, B(a)p plus LPS exposure significantly increased tumor incidence, mean tumor count and tumor size of visible tumors of lungs compared with B(a)p treatment alone, and NLRP3 deletion inhibited lung tumorigenesis induced by B(a)p or B(a)p plus LPS. Histopathological examination found LPS-induced pulmonary inflammatory changes enhanced lung tumorigenesis induced by B(a)p in WT mice, deletion of NLRP3 improved the inflammatory changes induced by LPS and the number and size of pathological tumor nests induced by B(a)p or B(a)p plus LPS. In addition, we found B(a)p treatment and B(a)p plus LPS treatment predominately induced the development of adenoma.ConclusionLPS enhanced B(a)p-induced lung tumorigenesis in WT and NLRP3−/− mice of C57BL/6J strain, and NLRP3 deletion inhibits lung tumorigenesis induced by B(a)p or B(a)p plus LPS.

Carcinogenesis: Failure of resolution of inflammation?

“…Helicobacter pylori , hepatitis B or C, Epstein-Barr virus, and other infections are associated with increased cancer risk and carcinogenesis ( Moss & Blaser, 2005 ). In a mouse model benzo( a )pyrene (BaP) and lipopolysaccharide (LPS) promote lung tumorigenesis ( Huang et al, 2019 ). Multiple liver infections including liver fluke and Clonorchis sinensis administered with NDMA cause experimental cholangiocarcinoma ( Kim, Bae, Choi, & Hong, 2019 ; Laothong et al, 2013 ).…”

Glyburide attenuates B(a)p and LPS‐induced inflammation‐related lung tumorigenesis in mice

“…In our previous study, we investigated the role of NLRP3 in mouse in ammation-related lung cancer initiation, and found that NLRP3 deletion inhibited lung cancer initiation induced by B(a)p or B(a)p plus LPS [7], we also found that NLRP3 in ammasome activation played an important role in B(a)p plus LPSinduced in ammation-related lung tumorigenesis in mice [8].…”

“…2 As an important and most investigated inflammatory regulator, NLRP3 inflammasome has been reported to have a key function in the occurrence of lung carcinoma, and recently studies show that inflammasomes may serve as preventing and treating cancer. 3,4 In our previous articles, we investigated the function of NLRP3 in inflammation-related lung carcinoma initiation, and found that the lack of NLRP3 inhibited B(a)p or B(a)p/LPS-related lung carcinoma initiation, 5 we also revealed that activated NLRP3 inflammasome could act on in lung cancer initiation in inflammation-related mice caused by B(a)p/LPS. 6 Glyburide, a NLRP3 inhibitor, plays an anti-inflammatory role to inhibit the NLRP3 inflammasome, decreases the production of proinflammatory cytokines, reduces the recruitment and migration of inflammatory cells, and production of nitricoxide.…”

Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer

“…Overexpression of IL-1β in lung adenocarcinoma (ADC) cells results in the promotion of experimental lung metastasis via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules [ 76 ]. In line with this, NLRP3 promotes the mouse lung tumorigenesis induced by benzo(a)pyrene and LPS [ 77 ] and favors experimental lung metastasis development by affecting the ability of host NK cells to control the tumor [ 78 ]. Polydatin, a natural component, suppresses the proliferation and migration of NSCLC cells via the NF-κB pathway, inhibiting NLRP3 inflammasome activation [ 136 , 137 ].…”