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Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice.

Lewkowich IP, Lajoie S, Clark JR, Herman NS, Sproles AA, Wills-Karp M - PLoS ONE (2008)

Bottom Line: Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs.Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness.Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT
Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs "pro-asthmatic", and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

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Adoptive transfer of mDCs to resistant mice induces AHR and IL-17 production similar to that seen in susceptible animals.C3H mice were sensitized with PBS-, or HDM-pulsed bone marrow-derived DCs on day 0. Mice were challenged with HDM or PBS on day 14 and sacrificed 72 hours later. AHR (A) and BAL cell composition (B) were examined at sacrifice. Lung cells were also stimulated with HDM in vitro, and cytokine production was assayed by ELISA (C). † and †† indicate significant differences (p<0.05 and p<0.001 respectively) compared to PBS-treated animals or PBS-pulsed DCs.
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pone-0003879-g008: Adoptive transfer of mDCs to resistant mice induces AHR and IL-17 production similar to that seen in susceptible animals.C3H mice were sensitized with PBS-, or HDM-pulsed bone marrow-derived DCs on day 0. Mice were challenged with HDM or PBS on day 14 and sacrificed 72 hours later. AHR (A) and BAL cell composition (B) were examined at sacrifice. Lung cells were also stimulated with HDM in vitro, and cytokine production was assayed by ELISA (C). † and †† indicate significant differences (p<0.05 and p<0.001 respectively) compared to PBS-treated animals or PBS-pulsed DCs.

Mentions: To determine if shifting the phenotype of mDCs involved in allergen presentation in resistant mice towards one of robust allergen uptake, high-level co-stimulatory molecule expression, and production of Th17-associated cytokines is sufficient to cause AHR in genetically resistant animals, we adoptively transferred 1×106 in vitro PBS- or HDM-pulsed C3H BMDCs to the airways of C3H mice on day 0, and challenged with PBS or HDM on day 14. Mice were sacrificed on day 17 to assess airway function, and pulmonary T cell cytokine expression. In C3H mice sensitized with PBS-pulsed dendritic cells, subsequent challenge with PBS or HDM, resulted in levels of AHR (Figure 8a), airway eosinophilia (Figure 8b), and HDM-restimulated Th2 cytokine production (Figure 8c) comparable to that seen in PBS-sensitized and challenged animals (compare to Figure 1a). In contrast, adoptive transfer of HDM-pulsed BMDCs induced robust AHR (Figure 8a), and airway eosinophilia (Figure 8b). Strikingly, the level of AHR induced in resistant C3H mice following sensitization with HDM-pulsed BMDCs was indistinguishable from that seen in HDM-exposed A/J mice (compare to Figure 1a). Lung cells from HDM-pulsed BMDC-sensitized C3H mice produced both Th2 (IL-4, IL-5, IL-13) and Th1 (IFNγ) cytokines (Figure 8c), similar to the pattern observed following sensitization with HDM, albeit ∼10-fold more intense (compare to Figure 1d). Interestingly, upon HDM-restimulation, lung cells from these BMDC-sensitized C3H mice produced levels of IL-17A 100-fold greater than those observed following intratracheal administration of HDM alone (Figure 8c). The concomitant induction of a Th17 response, similar to that observed in A/J mice treated with intratracheal HDM, is likely the result of elevated p19 and IL-6 production observed in adoptively transferred DCs (Figure 7c). Collectively, these results demonstrate that genetic resistance to allergen-induced AHR can be overcome by limiting the ability of pDCs to capture antigen and shifting the balance of antigen presentation towards highly activated, mDCs producing abundant Th17-skewing cytokines. Furthermore, these data also suggest that the pulmonary environment in which allergen encounter first takes place is of critical importance in directing the development of tolerance or allergen-induced AHR following initial allergen exposure.


Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice.

Lewkowich IP, Lajoie S, Clark JR, Herman NS, Sproles AA, Wills-Karp M - PLoS ONE (2008)

Adoptive transfer of mDCs to resistant mice induces AHR and IL-17 production similar to that seen in susceptible animals.C3H mice were sensitized with PBS-, or HDM-pulsed bone marrow-derived DCs on day 0. Mice were challenged with HDM or PBS on day 14 and sacrificed 72 hours later. AHR (A) and BAL cell composition (B) were examined at sacrifice. Lung cells were also stimulated with HDM in vitro, and cytokine production was assayed by ELISA (C). † and †† indicate significant differences (p<0.05 and p<0.001 respectively) compared to PBS-treated animals or PBS-pulsed DCs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2586658&req=5

pone-0003879-g008: Adoptive transfer of mDCs to resistant mice induces AHR and IL-17 production similar to that seen in susceptible animals.C3H mice were sensitized with PBS-, or HDM-pulsed bone marrow-derived DCs on day 0. Mice were challenged with HDM or PBS on day 14 and sacrificed 72 hours later. AHR (A) and BAL cell composition (B) were examined at sacrifice. Lung cells were also stimulated with HDM in vitro, and cytokine production was assayed by ELISA (C). † and †† indicate significant differences (p<0.05 and p<0.001 respectively) compared to PBS-treated animals or PBS-pulsed DCs.
Mentions: To determine if shifting the phenotype of mDCs involved in allergen presentation in resistant mice towards one of robust allergen uptake, high-level co-stimulatory molecule expression, and production of Th17-associated cytokines is sufficient to cause AHR in genetically resistant animals, we adoptively transferred 1×106 in vitro PBS- or HDM-pulsed C3H BMDCs to the airways of C3H mice on day 0, and challenged with PBS or HDM on day 14. Mice were sacrificed on day 17 to assess airway function, and pulmonary T cell cytokine expression. In C3H mice sensitized with PBS-pulsed dendritic cells, subsequent challenge with PBS or HDM, resulted in levels of AHR (Figure 8a), airway eosinophilia (Figure 8b), and HDM-restimulated Th2 cytokine production (Figure 8c) comparable to that seen in PBS-sensitized and challenged animals (compare to Figure 1a). In contrast, adoptive transfer of HDM-pulsed BMDCs induced robust AHR (Figure 8a), and airway eosinophilia (Figure 8b). Strikingly, the level of AHR induced in resistant C3H mice following sensitization with HDM-pulsed BMDCs was indistinguishable from that seen in HDM-exposed A/J mice (compare to Figure 1a). Lung cells from HDM-pulsed BMDC-sensitized C3H mice produced both Th2 (IL-4, IL-5, IL-13) and Th1 (IFNγ) cytokines (Figure 8c), similar to the pattern observed following sensitization with HDM, albeit ∼10-fold more intense (compare to Figure 1d). Interestingly, upon HDM-restimulation, lung cells from these BMDC-sensitized C3H mice produced levels of IL-17A 100-fold greater than those observed following intratracheal administration of HDM alone (Figure 8c). The concomitant induction of a Th17 response, similar to that observed in A/J mice treated with intratracheal HDM, is likely the result of elevated p19 and IL-6 production observed in adoptively transferred DCs (Figure 7c). Collectively, these results demonstrate that genetic resistance to allergen-induced AHR can be overcome by limiting the ability of pDCs to capture antigen and shifting the balance of antigen presentation towards highly activated, mDCs producing abundant Th17-skewing cytokines. Furthermore, these data also suggest that the pulmonary environment in which allergen encounter first takes place is of critical importance in directing the development of tolerance or allergen-induced AHR following initial allergen exposure.

Bottom Line: Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs.Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness.Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT
Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs "pro-asthmatic", and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

Show MeSH
Related in: MedlinePlus