title: Decreasing SMPD1 activity in BEAS-2B bronchial airway epithelial cells results in increased NRF2 activity, cytokine synthesis and neutrophil recruitment.
abstract: Niemann-Pick disease (NPD) type B is a rare autosomal recessive disease characterized by variable levels of impairment in sphingomyelin phosphodiesterase 1 (SMPD1) activity. Lung involvement is the most important prognostic factor in NPD-B, with recurrent respiratory infections starting in infancy being the major cause of morbidity and mortality. We hypothesized that decreased SMPD1 activity impaired airway epithelium host defense response. SMPD1 activity was reduced using inducible shRNA. Surprisingly, decreasing SMPD1 activity by 50%, resulted in increased neutrophil recruitment, both at baseline and in response to bacterial stimulation. This correlated with elevated levels of cytokine mRNA shown to contribute to neutrophil recruitment in unstimulated (e.g. IL-8 and GRO-α) and infected cells (e.g. IL-8, GRO-α, GM-CSF and CCL20). Instead of preventing the host defence responses, decreased SMPD1 activity results in an inflammatory response even in the absence of infection. Moreover, decreasing SMPD1 activity resulted in a pro-oxidative shift. Accordingly, expression of an inactive mutant, SMPD1[L225P] but not the WT enzyme increased activation of the antioxidant transcription factor NRF2. Therefore, decreasing SMPD1 activity by 50% in airway epithelial cells, the equivalent of the loss of one allele, results in the accumulation of oxidants that activates NRF2 and a concomitant increased cytokine production as well as neutrophil recruitment. This can result in a chronic inflammatory state that impairs host defence similar to scenarios observe in other chronic inflammatory lung disease such as Chronic Obstructive Pulmonary Disease or Cystic Fibrosis.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Elyse
authors.initials: E
authors.lastname: MacFadden-Murphy
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Martel
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Bérubé
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, McGill University Health Centre Research Institute, Montreal, Quebec, Canada. Electronic address: simon.rousseau@mcgill.ca.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000276:immunology*; D020556:Neutrophil Infiltration; D052537:Niemann-Pick Disease, Type B / Q000276:immunology*; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000276:immunology*
chemical_list: D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase
keywords: Acidic sphingomyelinase; Airway epithelium; Interleukins; Niemann-Pick disease; Pseudomonas aeruginosa; Reactive oxygen species