Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17.
Exposure to ozone, which is a major component of air pollution, induces a form of asthma that occurs in the absence of adaptive immunity. Although ozone-induced asthma is characterized by airway neutrophilia, and not eosinophilia, it is nevertheless associated with airway hyperreactivity (AHR), which is a cardinal feature of asthma. Because AHR induced by allergens requires the presence of natural killer T (NKT) cells, we asked whether ozone-induced AHR had similar requirements. We found that repeated exposure of wild-type (WT) mice to ozone induced severe AHR associated with an increase in airway NKT cells, neutrophils, and macrophages. Surprisingly, NKT cell-deficient (CD1d(-/-) and Jalpha18(-/-)) mice failed to develop ozone-induced AHR. Further, treatment of WT mice with an anti-CD1d mAb blocked NKT cell activation and prevented ozone-induced AHR. Moreover, ozone-induced, but not allergen-induced, AHR was associated with NKT cells producing interleukin (IL)-17, and failed to occur in IL-17(-/-) mice nor in WT mice treated with anti-IL-17 mAb. Thus, ozone exposure induces AHR that requires the presence of NKT cells and IL-17 production. Because NKT cells are required for the development of two very disparate forms of AHR (ozone- and allergen-induced), our results strongly suggest that NKT cells mediate a unifying pathogenic mechanism for several distinct forms of asthma, and represent a unique target for effective asthma therapy.
Pichavant
Muriel
M
Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Goya
Sho
S
Meyer
Everett H
EH
Johnston
Richard A
RA
Kim
Hye Y
HY
Matangkasombut
Ponpan
P
Zhu
Ming
M
Iwakura
Yoichiro
Y
Savage
Paul B
PB
DeKruyff
Rosemarie H
RH
Shore
Stephanie A
SA
Umetsu
Dale T
DT
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D007958:Leukocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage; D010126:Ozone / Q000633:toxicity*; D013601:T-Lymphocytes / Q000276:immunology*
D000393:Air Pollutants; D018793:Interleukin-13; D020381:Interleukin-17; D015847:Interleukin-4; D010126:Ozone; D010047:Ovalbumin