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

Li Huang,Wei Wang,Hong Liu,Yongjun Wu,Shuang Chen,Hua Shao,Jing Wang,Wu Yao,Feifei Feng,Peng Zhang,Aihua Zhang,Shuyin Duan,Qiao Zhang,Na Wang

doi:10.1186/s12931-019-0983-4

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.

Highlights

Lung cancer is the leading cause of cancer-related mortality, which accounts for one-quarter of all cancer deaths [1]
NLRP3 deletion inhibited lung tumorigenesis induced by B(a)p plus LPS in mice As shown in Fig. 2 and Fig. 3, mice 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
The lung tumor multiplicity of NLRP3−/− mice exposed to B(a)p or B(a)p plus LPS was significantly less than WT mice treated with B(a)p or B(a)p plus LPS, respectively (P < 0.05)

Summary

Introduction

Lung cancer is the leading cause of cancer-related mortality, which accounts for one-quarter of all cancer deaths [1]. The promoting role of inflammation in lung cancer has been reported [4, 5]. LPS-induced pulmonary inflammation could be a critical contributor to the induction of genotoxicity by B(a)p [12], the molecular mechanisms responsible for the enhancement of pulmonary inflammation in lung tumorigenesis have not been fully clarified. The promotive role of NLRP3 inflammasome in lung metastases, breast cancer and gastric carcinoma has been reported [19]. 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. 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

Methods

Results

Discussion

Conclusion