title: Nontypeable Haemophilus Influenzae Infection Upregulates the NLRP3 Inflammasome and Leads to Caspase-1-Dependent Secretion of Interleukin-1β - A Possible Pathway of Exacerbations in COPD.
abstract: Nontypeable Haemophilus influenzae (NTHi) is the most common cause for bacterial exacerbations in chronic obstructive pulmonary disease (COPD). Recent investigations suggest the participation of the inflammasome in the pathomechanism of airway inflammation. The inflammasome is a cytosolic protein complex important for early inflammatory responses, by processing Interleukin-1β (IL-1β) to its active form.
  
  
  
  Since inflammasome activation has been described for a variety of inflammatory diseases, we investigated whether this pathway plays a role in NTHi infection of the airways.
  
  
  
  A murine macrophage cell line (RAW 264.7), human alveolar macrophages and human lung tissue (HLT) were stimulated with viable or non-viable NTHi and/or nigericin, a potassium ionophore. Secreted cytokines were measured with ELISA and participating proteins detected via Western Blot or immunohistochemistry.
  
  
  
  Western Blot analysis of cells and immunohistochemistry of lung tissue detected the inflammasome key components NLRP3 and caspase-1 after stimulation, leading to a significant induction of IL-1β expression (RAW: control at the lower detection limit vs. NTHi 505±111pg/ml, p<0.01). Inhibition of caspase-1 in human lung tissue led to a significant reduction of IL-1β and IL-18 levels (IL-1β: NTHi 24 h 17423±3198pg/ml vs. NTHi+Z-YVAD-FMK 6961±1751pg/ml, p<0.01).
  
  
  
  Our data demonstrate the upregulation of the NRLP3-inflammasome during NTHi-induced inflammation in respiratory cells and tissues. Our findings concerning caspase-1 dependent IL-1β release suggest a role for the inflammasome in respiratory tract infections with NTHi which may be relevant for the pathogenesis of bacterial exacerbations in COPD.
authors.affiliation: Medical Clinic III, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Rotta Detto Loria
authors.forename: Kristina
authors.initials: K
authors.lastname: Rohmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Droemann
authors.forename: Peter
authors.initials: P
authors.lastname: Kujath
authors.forename: Jan
authors.initials: J
authors.lastname: Rupp
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Dalhoff
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D006190:Haemophilus / Q000502:physiology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D050296:Microbial Viability; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000382:microbiology*; D000067996:RAW 264.7 Cells; D015854:Up-Regulation
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020170:Caspase 1