Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization.
Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.
Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
M J
MJ
Gold
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
P R
PR
Hiebert
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
H Y
HY
Park
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
D
D
Stefanowicz
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
A
A
Le
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
M R
MR
Starkey
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
A
A
Deane
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
A C
AC
Brown
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
G
G
Liu
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
J C
JC
Horvat
Discipline of Pharmacy, Graduate School of Health, The University of Technology Sydney, Sydney, Australia.|Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Sydney, Australia.
Z A
ZA
Ibrahim
Discipline of Pharmacy, Graduate School of Health, The University of Technology Sydney, Sydney, Australia.|Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Sydney, Australia.
M B
MB
Sukkar
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
P M
PM
Hansbro
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Vancouver Coastal Health Research Institute, Vancouver General Hospital, Vancouver, British Columbia, Canada.
C
C
Carlsten
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
S
S
VanEeden
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
D D
DD
Sin
Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
K M
KM
McNagny
Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.|School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia.|Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
D A
DA
Knight
James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Vancouver Coastal Health Research Institute, Vancouver General Hospital, Vancouver, British Columbia, Canada.
J A
JA
Hirota
D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D018928:Immunity, Mucosal; D007114:Immunization; D008168:Lung / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052638:Particulate Matter / Q000276:immunology*; D039981:Pyroglyphidae; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014527:Uric Acid / Q000378:metabolism*
D039741:Antigens, Dermatophagoides; D052638:Particulate Matter; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014527:Uric Acid