title: Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice.
abstract: BACKGROUND
  Mycoplasma pneumoniae (Mp) frequently colonizes the airways of patients with chronic asthma and likely contributes to asthma exacerbations. We previously reported that mice lacking surfactant protein A (SP-A) have increased airway hyperresponsiveness (AHR) during M pneumoniae infection versus wild-type mice mediated by TNF-α. Mast cells (MCs) have been implicated in AHR in asthma models and produce and respond to TNF-α.
  
  
  OBJECTIVE
  Determine the contribution of MC/TNF interactions to AHR in airways lacking functional SP-A during Mp infection.
  
  
  METHODS
  Bronchoalveolar lavage fluid was collected from healthy and asthmatic subjects to examine TNF-α levels and M pneumoniae positivity. To determine how SP-A interactions with MCs regulate airway homeostasis, we generated mice lacking both SP-A and MCs (SP-A(-/-)Kit(W-sh/W-sh)) and infected them with M pneumoniae.
  
  
  RESULTS
  Our findings indicate that high TNF-α levels correlate with M pneumoniae positivity in human asthmatic patients and that human SP-A inhibits M pneumoniae-stimulated transcription and release of TNF-α by MCs, implicating a protective role for SP-A. MC numbers increase in M pneumoniae-infected lungs, and airway reactivity is dramatically attenuated when MCs are absent. Using SP-A(-/-)Kit(W-sh/W-sh) mice engrafted with TNF-α(-/-) or TNF receptor (TNF-R)(-/-) MCs, we found that TNF-α activation of MCs through the TNF-R, but not MC-derived TNF-α, leads to augmented AHR during M pneumoniae infection when SP-A is absent. Additionally, M pneumoniae-infected SP-A(-/-)Kit(W-sh/W-sh) mice engrafted with TNF-α(-/-) or TNF-R(-/-) MCs have decreased mucus production compared with that seen in mice engrafted with wild-type MCs, whereas burden was unaffected.
  
  
  CONCLUSIONS
  Our data highlight a previously unappreciated but vital role for MCs as secondary responders to TNF-α during the host response to pathogen infection.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Bethany J
authors.initials: BJ
authors.lastname: Hsia
authors.forename: Julie G
authors.initials: JG
authors.lastname: Ledford
authors.forename: Erin N
authors.initials: EN
authors.lastname: Potts-Kant
authors.forename: Vinayak S
authors.initials: VS
authors.lastname: Nikam
authors.forename: Njira L
authors.initials: NL
authors.lastname: Lugogo
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
authors.forename: Soman N
authors.initials: SN
authors.lastname: Abraham
authors.forename: Jo Rae
authors.initials: JR
authors.lastname: Wright
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D006801:Humans; D008168:Lung / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009177:Mycoplasma pneumoniae / Q000276:immunology / Q000472:pathogenicity*; D011019:Pneumonia, Mycoplasma / Q000276:immunology* / Q000503:physiopathology; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency* / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D037662:Pulmonary Surfactant-Associated Protein A; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha