Interleukin-1 receptor and caspase-1 are required for the Th17 response in nitrogen dioxide-promoted allergic airway disease.
Nitrogen dioxide (NO2) is an environmental pollutant and endogenously generated oxidant associated with the development, severity, and exacerbation of asthma. NO2 exposure is capable of allergically sensitizing mice to the innocuous inhaled antigen ovalbumin (OVA), promoting neutrophil and eosinophil recruitment, and a mixed Th2/Th17 response upon antigen challenge that is reminiscent of severe asthma. However, the identity of IL-17A-producing cells and the mechanisms governing their ontogeny in NO2-promoted allergic airway disease remain unstudied. We measured the kinetics of lung inflammation after antigen challenge in NO2-promoted allergic airway disease, including inflammatory cells in bronchoalveolar lavage and antigen-specific IL-17A production from the lung. We determined that IL-17A(+) cells were predominately CD4(+)T cell receptor (TCR)β(+) Th17 cells, and that a functional IL-1 receptor was required for Th17, but not Th2, cytokine production after in vitro antigen restimulation of lung cells. The absence of natural killer T cells, γδ T cells, or the inflammasome scaffold nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain (Nlrp)3 did not affect the development of NO2-promoted allergic inflammation or IL-17A production. Similarly, neutrophil depletion or the neutralization of IL-1α during sensitization exerted no effect on these parameters. However, the absence of caspase-1 significantly reduced IL-17A production from lung cells without affecting Th2 cytokines or lung inflammation. Finally, the intranasal administration of IL-1β and the inhalation of antigen promoted allergic sensitization that was reflected by neutrophilic airway inflammation and IL-17A production from CD4(+)TCRβ(+) Th17 cells subsequent to antigen challenge. These data implicate a role for caspase-1 and IL-1β in the IL-1 receptor-dependent Th17 response manifest in NO2-promoted allergic airway disease.
Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
Rebecca A
RA
Martin
Jennifer L
JL
Ather
Lennart K A
LK
Lundblad
Benjamin T
BT
Suratt
Jonathan E
JE
Boyson
Ralph C
RC
Budd
John F
JF
Alcorn
Richard A
RA
Flavell
Stephanie C
SC
Eisenbarth
Matthew E
ME
Poynter
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D004804:Eosinophils / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D009585:Nitrogen Dioxide / Q000633:toxicity*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*
D000393:Air Pollutants; D018836:Inflammation Mediators; D020381:Interleukin-17; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017472:Receptors, Interleukin-1; D020170:Caspase 1; D009585:Nitrogen Dioxide