IL-1β Promotes Inflammatory Cell Infiltration By Activating ADAMTS4 Release From Fibroblasts In CRSwNP

Background:Increase of inflammatory cell infiltration is a hallmark of chronic rhinosinusitis with nasal polyps(CRSwNPs),leading to enhanced inflammation and poor prognosis of nasal polyps(NPs).ADAMTS4(a disintegrin and metallopeptidase with thrombospondin type 1 motif 4)is considered to play an important role in immune cell infiltration during airway inflammation,but its role in CRSwNP remains unknown.Objectives:The goal of this study was to investigate the expression and regulation of ADAMTS4 in CRSwNP,and the role it plays in inflammatory cell infiltration.Methods:NP tissues from CRSwNP patients and inferior turbinate(IT)tissues from patients with septal deviation were obtained during endoscopic surgery.The expressions of ADAMTS4,IL-1β,and ITGA5(Integrin Subunit Alpha 5)were assessed by quantitative RT-PCR,Immunofluorescence,and Western blotting.Regulation of ADAMTS4 expression was explored by using cultured primary human fibroblasts which was purified from nasal polyps and inferior turbinate,respectively.The inflammatory cell counts were also evaluated and their correlation with ADAMTS4 expression was analyzed.Results:Gene expression analysis and Western Blot revealed that nasal polyps display increased level of IL-1β,ITGA5,and ADAMTS4 compared with control samples.Immunofluorescence confirmed that ADAMTS4 was predominantly expressed by ITGA5 positive fibroblasts in NPs,which was positive correlated with the up-regulated IL-1β.Fibroblasts derived from NPs displayed higher ITGA5 and ADAMTS4 expression than those derived from inferior turbinate.IL-1β promoted activation of fibroblasts,and up-regulated ADAMTS4 expression in fibroblasts derived from in NPs.ADAMTS4 expression was positively correlated with tissue eosinophil and neutrophil numbers in patients with CRSwNP.Conclusion:Over-expression of IL-1β up-regulates ADAMTS4 expression in ITGA5 positive fibroblasts,which may enhance eosinophils and neutrophils infiltration in nasal polyps and predict poor prognosis of CRSwNP patients.