title: Inflammasome Inhibition Suppresses Alveolar Cell Permeability Through Retention of Neuregulin-1 (NRG-1).
abstract: BACKGROUND
  Neuregulin (NRG)-1-human epidermal receptor (HER)-2 signaling pathway is a key regulator of IL-1β-mediated pulmonary inflammation and epithelial permeability. The inflammasome is a newly discovered molecular platform required for caspase-1 activation and maturation of IL-1β. However, the role of the inflammasome in NRG-1-HER2 signaling-mediated alveolar cell permeability is unknown.
  
  
  METHODS
  The inflammasome was activated or inhibited in THP-1 cells; supernatants from these cells were added to A549 cells and human small airway epithelial cells (HSAEC). The protein expression of NRG-1 and phospho-HER2 (pHER2) were measured by Western blot analysis and epithelial permeability was measured using Lucifer yellow dye.
  
  
  RESULTS
  Results reveal that alveolar permeability in A549 cells and HSAEC is increased when treated with supernatants of inflammasome-activated THP-1 cells. Alveolar permeability is significantly suppressed when treated with supernatant of inflammasome-inhibited THP-1 cells. Inflammasome-mediated permeability is decreased when A549 cells and HSAEC are pretreated with IL-1β receptor antagonist (IL-1βRA). In addition, HER2 kinase inhibitor AG825 or NRG-1 inhibitor TAPI inhibits inflammasome-mediated permeability in A549 cells and HSAEC demonstrating critical roles of IL-1β, NRG-1, and HER2 in inflammasome-mediated alveolar permeability.
  
  
  CONCLUSIONS
  These findings suggest that inflammasome-induced alveolar cell permeability is mediated by NRG-1/HER2 signaling through IL-1β regulation.
authors.affiliation: Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa FL, USA.
authors.forename: Rajanbabu
authors.initials: R
authors.lastname: Venugopal
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Galam
authors.forename: Ruan
authors.initials: R
authors.lastname: Cox
authors.forename: Jutaro
authors.initials: J
authors.lastname: Fukumoto
authors.forename: Young
authors.initials: Y
authors.lastname: Cho
authors.forename: Prasanna Tamarapu
authors.initials: PT
authors.lastname: Parthasarathy
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lockey
authors.forename: Narasaiah
authors.initials: N
authors.lastname: Kolliputi
mesh_terms: D045744:Cell Line, Tumor; D018734:Genes, erbB-2; D006801:Humans; D058847:Inflammasomes; D053583:Interleukin-1beta / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism*; D011650:Pulmonary Alveoli
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; C094131:NRG1 protein, human; D020890:Neuregulin-1