Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells.
Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D(2) binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3(+) CD4(+) regulatory T cells that suppressed inflammation in an interleukin 10-dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.
Hammad
Hamida
H
Department of Pulmonary Medicine, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands.
Kool
Mirjam
M
Soullié
Thomas
T
Narumiya
Shuh
S
Trottein
François
F
Hoogsteden
Henk C
HC
Lambrecht
Bart N
BN
D000534:Alum Compounds / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000633:toxicity; D015230:Prostaglandin D2 / Q000276:immunology* / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D000534:Alum Compounds; D011982:Receptors, Prostaglandin; C446402:ovalbumin-alum; D016753:Interleukin-10; D010047:Ovalbumin; D017868:Cyclic AMP-Dependent Protein Kinases; D015230:Prostaglandin D2