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Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells.

Hammad H, Kool M, Soullié T, Narumiya S, Trottein F, Hoogsteden HC, Lambrecht BN - J. Exp. Med. (2007)

Bottom Line: Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells.These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A.Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands.

ABSTRACT
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.

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Administration of BW245C affects lung myeloid DCs and inhibits airway inflammation. On day 0, mice received an i.t. injection of OVA in the presence or in the absence of BW245C. From days −1 to 2, mice were injected i.p. with anti–Gr-1 antibodies to deplete pDCs or isotype control antibodies. 10 d later, mice were exposed to three OVA aerosols. (A) BAL fluid was analyzed by flow cytometry. Data are shown as mean ± SEM. (B) May Grunwald Giemsa staining of lung sections. Bar, 85 μm .
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fig4: Administration of BW245C affects lung myeloid DCs and inhibits airway inflammation. On day 0, mice received an i.t. injection of OVA in the presence or in the absence of BW245C. From days −1 to 2, mice were injected i.p. with anti–Gr-1 antibodies to deplete pDCs or isotype control antibodies. 10 d later, mice were exposed to three OVA aerosols. (A) BAL fluid was analyzed by flow cytometry. Data are shown as mean ± SEM. (B) May Grunwald Giemsa staining of lung sections. Bar, 85 μm .

Mentions: To prove more directly that DP1 ligation can suppress the function of lung DCs in vivo, we used a model in which Th2 sensitization depends on endogenous lung myeloid (m)DCs (20). Mice were first depleted of tolerogenic plasmacytoid (p)DCs by treatment with anti–Gr-1 antibodies, thus leading to priming to inhaled harmless OVA. In Gr-1–treated mice, but not in control mice, OVA inhalation led to strong airway eosinophilia and lymphocytosis (Fig. 4, A and B). Mice treated with BW245C at the time of OVA priming no longer developed signs of airway inflammation. To rule out any indirect effects of BW245C on lung structural cells, we performed experiments in which BM-derived mDCs were treated in vitro with BW245C before adoptive transfer to the airways in vivo, a protocol leading to Th2 sensitization and features of asthma in BALB/c and C57BL/6 mice (19 and Fig. 5, A and B). The pretreatment of OVA-DCs with BW245C inhibited their capacity to prime for airway inflammation and Th2 responses in the MLN in a DP1-dependent way (Fig. 5 B). BW245C-pretreated OVA-DCs induced higher levels of IL-10 and IFN-γ compared with vehicle. Strikingly, OVA-DCs from DP1−/− mice were consistently more effective at inducing airway inflammation compared with WT DCs and also induced the highest levels of IL-5 in the LN. Analogous to treatment in vivo (Fig. 1 E), pretreatment of WT OVA-DCs with BW245C led to an increase in the percentage of CD4+CD25+Foxp3+ T cells and IL-10+ T cells in the MLNs; the latter effects were dependent on DP1 (Fig. 5 C).


Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells.

Hammad H, Kool M, Soullié T, Narumiya S, Trottein F, Hoogsteden HC, Lambrecht BN - J. Exp. Med. (2007)

Administration of BW245C affects lung myeloid DCs and inhibits airway inflammation. On day 0, mice received an i.t. injection of OVA in the presence or in the absence of BW245C. From days −1 to 2, mice were injected i.p. with anti–Gr-1 antibodies to deplete pDCs or isotype control antibodies. 10 d later, mice were exposed to three OVA aerosols. (A) BAL fluid was analyzed by flow cytometry. Data are shown as mean ± SEM. (B) May Grunwald Giemsa staining of lung sections. Bar, 85 μm .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118726&req=5

fig4: Administration of BW245C affects lung myeloid DCs and inhibits airway inflammation. On day 0, mice received an i.t. injection of OVA in the presence or in the absence of BW245C. From days −1 to 2, mice were injected i.p. with anti–Gr-1 antibodies to deplete pDCs or isotype control antibodies. 10 d later, mice were exposed to three OVA aerosols. (A) BAL fluid was analyzed by flow cytometry. Data are shown as mean ± SEM. (B) May Grunwald Giemsa staining of lung sections. Bar, 85 μm .
Mentions: To prove more directly that DP1 ligation can suppress the function of lung DCs in vivo, we used a model in which Th2 sensitization depends on endogenous lung myeloid (m)DCs (20). Mice were first depleted of tolerogenic plasmacytoid (p)DCs by treatment with anti–Gr-1 antibodies, thus leading to priming to inhaled harmless OVA. In Gr-1–treated mice, but not in control mice, OVA inhalation led to strong airway eosinophilia and lymphocytosis (Fig. 4, A and B). Mice treated with BW245C at the time of OVA priming no longer developed signs of airway inflammation. To rule out any indirect effects of BW245C on lung structural cells, we performed experiments in which BM-derived mDCs were treated in vitro with BW245C before adoptive transfer to the airways in vivo, a protocol leading to Th2 sensitization and features of asthma in BALB/c and C57BL/6 mice (19 and Fig. 5, A and B). The pretreatment of OVA-DCs with BW245C inhibited their capacity to prime for airway inflammation and Th2 responses in the MLN in a DP1-dependent way (Fig. 5 B). BW245C-pretreated OVA-DCs induced higher levels of IL-10 and IFN-γ compared with vehicle. Strikingly, OVA-DCs from DP1−/− mice were consistently more effective at inducing airway inflammation compared with WT DCs and also induced the highest levels of IL-5 in the LN. Analogous to treatment in vivo (Fig. 1 E), pretreatment of WT OVA-DCs with BW245C led to an increase in the percentage of CD4+CD25+Foxp3+ T cells and IL-10+ T cells in the MLNs; the latter effects were dependent on DP1 (Fig. 5 C).

Bottom Line: Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells.These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A.Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus