Abstract
BackgroundChronic rhinosinusitis (CRS), commonly divided into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) is an inflammatory disease which mechanism remain unclear. Leucine-rich repeat kinase 2 (LRRK2) has been proved to be a negative regulator of inflammation response while its role in pathogenesis of CRS has yet to be revealed. This research study was designed to investigate the relationship between the expression level and biologic role of LRRK2 in CRS.MethodsExpression of LRRK2 mRNA and noncoding repressor of NFAT (NRON) were examined by qRT-PCR. Protein levels of LRRK2 were performed by western blot and immunohistochemistry. Nuclear factor of activated T cells (NFAT) nuclear translocation was analyzed by immunohistochemistry. Additionally, LRRK2 mRNA and NRON expression in response to specific inflammatory stimulation was measured in human nasal epithelia cells (HNECs).ResultsThe expression of LRRK2 was increased in CRSsNP patients (p < 0.05) and positively correlated with the expression levels of CD3 and Charot-Leyden crystal. Meanwhile, the NRON expression level is much lower in CRSsNP patients compared to both the control group and CRSwNP group (p < 0.05). Marked enhanced NFAT nuclear localization was observed in CRSwNP groups compared with the CRSsNP and control group (p < 0.0001). And the over-expression of LRRK2 was significantly regulated by lipopolysaccharide (LPS) in HNECs (p < 0.05). Moreover, IL-17A can increase LRRK2 expression and suppress NRON expression in vitro and dexamethasone can rescue the NRON inhibition.ConclusionLRRK2 and NRON may play different role in CRSsNP and CRSwNP. The molecular mechanisms identified here may aid in the design of novel therapeutic strategies to improve clinical outcomes.
Highlights
Chronic rhinosinusitis (CRS), commonly divided into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) is an inflammatory disease which mechanism remain unclear
noncoding repressor of Nuclear factor of activated T cells (NFAT) (NRON) and Leucine-rich repeat kinase 2 (LRRK2) mRNA levels in nasal tissues As showed in Fig. 1a, significant upregulation of LRRK2 mRNA levels was found in CRSsNP groups but not in CRSwNP groups compared with the control group (p < 0.0001), and NRON levels were significantly higher in the inferior turbinate than in the middle turbinate of CRSsNP groups (p < 0.0001) and in NPs (p < 0.01) (Fig. 1b)
The cytoplasmic or nuclear staining of LRRK2 was mainly located at the Detection of LRRK2 producing cells in nasal mucosa These results revealed that LRRK2+ cells were highly accumulated in the submucosal region of CRSsNP tissues and that the mRNA and protein expression levels of LRRK2 were significantly higher in CRSsNP tissues (Fig. 2)
Summary
Chronic rhinosinusitis (CRS), commonly divided into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) is an inflammatory disease which mechanism remain unclear. Leucine-rich repeat kinase 2 (LRRK2) has been proved to be a negative regulator of inflammation response while its role in pathogenesis of CRS has yet to be revealed. Chronic rhinosinusitis (CRS) is an inflammatory disease that is composed of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). Their pathogenesis is not yet clear, it is commonly acknowledged that the two types of CRS possess distinct inflammation and remodeling patterns [1, 2]. Enhanced nuclear location of NFAT was associated with more severe colitis in LRRK2-deficient mice [14]
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