Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice.
Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca²⁺ entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca²⁺ signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient (Trpc1(-/-)) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1(-/-) splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1(-/-) mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.
Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
Eda
E
Yildirim
Michelle A
MA
Carey
Jeffrey W
JW
Card
Alexander
A
Dietrich
Gordon P
GP
Flake
Yingpei
Y
Zhang
J Alyce
JA
Bradbury
Yvette
Y
Rebolloso
Dori R
DR
Germolec
Daniel L
DL
Morgan
Darryl C
DC
Zeldin
Lutz
L
Birnbaumer
D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D005260:Female; D007376:Interleukin-2; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology; D050052:TRPC Cation Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*
D000485:Allergens; D007376:Interleukin-2; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1