NLRP3 Inflammasome Promotes The Development Of Allergic Rhinitis

Background:Allergic rhinitis(AR)has been recognized as one of the worldwide highly prevalent nasal inflamatory diseases with multiple clinical symptoms and complications,which severely disturbs the normal life and quality of human beings.Currently,the mechanisms underlying the development and regulation of AR are still elusive,with an intense concentration on the regulation of adaptive immune response.However,the roles of innate immune response in the AR progression has not been thoroughly studied,especially lack of clinical treatment targeting inflammatory response.Therefore,the regulatory mechanism for maintaining chronic inflammation during AR development is of great importance.Production of IL-1? resulting from excessive activation of inflammasome plays criticle roles in many chronic inflammatory diseases.And inflammasome activation and its associated amplification loop of inflammation attract much attention.Recent studies show that Asc-specks,a key adaptor of inflammasome,could induce cell pyrosis through endocytosis in a form similar to paracrine,which then forms the amplification loop of inflammasome to promote the inflammation response in the nasal microenviroment.Objective:To explore the roles of NLRP3 inflammasome activation in the development of AR,reveal its potential molecular mechanism,and provide novel approaches and targets for early intervention and clinical treatment of AR.Methods:1.Analysis of the clinical specimens: The production of IL-1? and IL-18 in the nasal lavage fluid of AR patients and controls were measured.IHC analysis of the caspase-1 expression and IL-1? production in the nasal mucosal tissue was conducted.2.Animal model analysis: 1)The inflammasome activation in the nasal mucosal tissue of OVA-induced AR mice was detected.2)The AR symptoms,serum IgE concentration,inflammasome activation and inflammatory cytokines in the nasal mucosal tissue between NLRP3 knockout mice and WT mice after OVA induction were compared.3)The AR symptoms,serum IgE concentration,inflammasome activation and inflammatory cytokines in the nasal mucosal tissue between caspase-1 inhibitor-treated mice and controls after OVA induction were compared.3.Cell line experiment: The classic activation of NLRP3 inflammasome was applied to collect ASC-specks,which next stimulated LPS-primed BEAS-2B cells.Thus,the cell model of the inflammatory nasal mucosal microenvironment was constrcted.Cell viability of BEAS-2B cells and intracellular inflammasome activation were measured.Results:1.Compared with the control group,the production of IL-1? and IL-18 in nasal lavage fluid of AR patients was significantly increased,and the caspase-1 expression and IL-1? production in nasal mucosal tissue were also increased.2.The production of IL-1?,expression of cleaved caspase-1 and cleaved IL-1? were increased in the nasal mucosal tissue of OVA-induced AR mice compared with those of controls.3.The AR symptoms were relieved,production of IL-1?,IL-6,IL-4,IL-5 and IL-13,expression of Cxcl9 and Cxcl10,expression of Ear1,expression of cleaved caspase-1,cleaved IL-1? and Gasdermin D were reduced,and the serum concentration of IgE unaltered in the nasal mucosal tissue of NLRP3 knockout mice than those of WT mice applied OVA-induced AR model.4.The AR symptoms were relieved,production of IL-1?,IL-6,IL-4,IL-5 and IL-13,expression of Cxcl9 and Cxcl10,expression of Ear1,expression of cleaved caspase-1 and cleaved IL-1? were reduced,and the serum concentration of IgE unaltered in the nasal mucosal tissue of caspase-1 inhibitor-treated mice than those of controls applied OVA-induced AR model.5.The LDH release and production of IL-1? were increased in the supernatant of LPS-primed BEAS-2B cells after ASC-specks stimulation.The expression of cleaved caspase-1,cleaved IL-1? and Gasdermin D were increased in the nasal mucosal tissue of LPS-primed BEAS-2B cells after ASC-specks stimulation.Conclusion:In this study,we find that inflammasome activation is enhanced in the nasal mucosal tissue both in AR patients and OVA-induced AR mice compared with that of controls.Furthermore,NLRP3 deficiency significantly inhibits the development and progression of IgE-independent AR with alleviative inflammatory response and reduced cell pyroptosis in the nasal mucosal tissue.And caspase-1 inhibitor treatment effectively relieves the IgE-independent AR symptoms and reduces the inflammation in the nasal mucosal tissue.Moreover,mechanistical study shows that ASC-specks over-accumulation and its associated nasal epithelium pyroptosis could promote the injury of nasal mucosa during AR development.These results suggest the crucial roles of NLRP3 inflammasome in promoting the development and progression of IgE-independent AR,which is demonstrated by NLRP3 knockout mice and caspase-1 specific inhibitor treatment in vivo,and provide novel approaches and targets for early intervention and clinical treatment of AR,especially IgE-independent AR.