title: Mesenchymal stromal cells mediate Aspergillus hyphal extract-induced allergic airway inflammation by inhibition of the Th17 signaling pathway.
abstract: Systemic administration of mesenchymal stromal cells (MSCs) suppresses airway inflammation and methacholine-induced airway hyper-responsiveness (AHR) in mouse models of T helper cell (Th) type 2-mediated eosinophilic allergic airway inflammation (AAI); however, the efficacy of MSCs in mouse models of severe Th17-mediated neutrophilic AAI has not yet been demonstrated. We assessed MSC effects in a mouse model of mixed Th2/Th17 AAI produced by mucosal exposure to Aspergillus fumigatus hyphal extract (AHE). Following sensitization produced by oropharyngeal AHE administration, systemic (tail vein) administration of syngeneic MSCs on the first day of challenge significantly reduced acute AHR predominantly through reduction of Th17-mediated airway inflammation. In parallel experiments, MSCs also mitigated AHR when administered during recurrent challenge 10 weeks after initial sensitization and challenge through reduction in systemic Th17-mediated inflammation. Investigation into potential mechanistic actions of MSCs in this model demonstrated that although T regulatory cells were increased in all AHE-treated mice, MSC administration did not alter T regulatory cell numbers in either the acute or recurrent model. Differential induction of interleukin-17a secretion was observed in ex vivo restimulation of mediastinal lymph node mixed-cell cytokine analyses. Although the mechanisms by which MSCs act to decrease inflammation and AHR in this model are not yet fully elucidated, decrease in Th17-mediated airway inflammation appears to play a significant role. These results provide a basis for further investigations of MSC administration as a potential therapeutic approach for severe refractory neutrophilic asthma.
authors.affiliation: Pulmonary Disease & Critical Care Medicine, Department of Medicine, University of Vermont, Burlington, Vermont, USA; Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Lathrop
authors.forename: Elice M
authors.initials: EM
authors.lastname: Brooks
authors.forename: Nick R
authors.initials: NR
authors.lastname: Bonenfant
authors.forename: Dino
authors.initials: D
authors.lastname: Sokocevic
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Borg
authors.forename: Meagan
authors.initials: M
authors.lastname: Goodwin
authors.forename: Roberto
authors.initials: R
authors.lastname: Loi
authors.forename: Fernanda
authors.initials: F
authors.lastname: Cruz
authors.forename: Chad W
authors.initials: CW
authors.lastname: Dunaway
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D001232:Aspergillus fumigatus / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17
keywords: Cell therapy; Lung asthma; Mesenchymal stromal cell; Mouse