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See detailMyeloid Hif1alpha counteracts allergic airway sensitization in mice through macrophage-mediated immunoregulation
Toussaint, Marie ULg; Fievez, Laurence ULg; Drion, Pierre ULg et al

in Abstract book of Keystone Symposium "Myeloid Cells: Regulation and Inflammation" (2013)

Hypoxia Inducible Factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid ... [more ▼]

Hypoxia Inducible Factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. In contrast, we observed that mice conditionally deficient for Hif1alpha in myeloid cells display enhanced sensitivity to the development of airway allergy to the experimental allergen ovalbumin as well as to house dust mite antigens. Following allergen exposure, these mice indeed developed enhanced allergen-specific T cell responses due to augmented activation of lung dendritic cells. Further analyses supported the idea that upon allergen exposure, MyD88-dependent upregulation of Hif1alpha boosts the expression of the immunosuppressive cytokine Interleukin (IL)-10 by lung interstitial macrophages. Interstitial macrophage-derived IL-10 in turn counteracts allergen-induced lung dendritic cell activation, consequently preventing the development of allergen-specific T cell responses. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1alpha possesses immunoregulatory functions implicated in the prevention of airway allergy. [less ▲]

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See detailMyeloid hypoxia-inducible factor 1alpha prevents airway allergy in mice through macrophage-mediated immunoregulation
Toussaint, Marie ULg; Fievez, Laurence ULg; Drion, Pierre ULg et al

in Mucosal Immunology (2013), 6(3), 485-97

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid ... [more ▼]

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1alpha in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. By contrast, we report here that mice conditionally deficient for Hif1alpha in myeloid cells display enhanced sensitivity to the development of airway allergy to experimental allergens and house-dust mite antigens. We support that upon allergen exposure, MyD88-dependent upregulation of Hif1alpha boosts the expression of the immunosuppressive cytokine interleukin (IL)-10 by lung interstitial macrophages (IMs). Hif1alpha-dependent IL-10 secretion is required for IMs to block allergen-induced dendritic cell activation and consequently for preventing the development of allergen-specific T-helper cell responses upon allergen exposure. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1alpha possesses immunoregulatory functions implicated in the prevention of airway allergy. [less ▲]

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See detailEtude du rôle de l’Hypoxia Inductible Facteur 1 dans les cellules myéloïdes lors d'allergie des voies respiratoires
Toussaint, Marie ULg

Doctoral thesis (2012)

Adaptive Th2 immune responses play a major orchestrating role in the development of airway allergy in mammals. It is currently known that the induction of Th2 responses closely depends on the activation ... [more ▼]

Adaptive Th2 immune responses play a major orchestrating role in the development of airway allergy in mammals. It is currently known that the induction of Th2 responses closely depends on the activation of innate immunity. Through its action on innate immune cells, Hypoxia inducible factor 1 (Hif1) has been described as a major regulator of inflammatory responses. Airway allergy is a disease whose incidence is in constant increase in developed countries, and the potential implication of Hif1 in innate immune cells during the development of such disease remains currently unknown. Therefore, we were interested in the involvement of Hif1 within innate immune cells in two experimental models of allergic airway inflammation: allergic asthma and recurrent airway obstruction (RAO). Recurrent airway obstruction is one of the most frequent respiratory syndrome that veterinary equine practice has to deal with in our countries. In the case of RAO, the role of the innate immune system, representing the first line of host defense, has not been investigated so far. We have therefore looked at the potential implication of Hif1 in pulmonary innate immune cells during this disease. We have found that, upon allergenic challenge, Hif1 expression within pulmonary innate immune cells was significantly increased in RAO-affected horses in comparison to the control animals. In addition, Hif1 expression was positively correlated to the severity of clinical dysfunctions in RAO-affected horses. We have also shown that the presence of hay-derived LPS could specifically increase Hif1 expression in macrophages. As previously described in other models of inflammation, these results allowed us to show, in a model of RAO, that Hif1 plays a pro-inflammatory role in innate immune cells. Since 90% of innate immune cells of a healthy horse are macrophages, we decided to further investigate the implication of Hif1 in lung myeloid cells. In the second study, for technical reasons, we decided to focus on another model of airway allergy, namely allergic asthma. Although molecular and cellular mechanisms governing asthma development are well characterized, very few information is available regarding the mechanisms that can prevent the development of this disease in healthy subjects. The identification of such mechanisms could be key to understand the origin of development of that epidemic disease as well as to improve the strategies of prevention. We have found that mice that were specifically deficient in Hif1 within myeloid cells (Hif1αm-/-) developed significantly more allergic inflammation in comparison to control mice. We have further shown that these mice had a higher inclination to develop a Th2 response upon allergenic challenge. We then proved that the increase of antigen-specific Th2 responses in Hif1αm-/- mice was the result of increased lymph node dendritic cells migration and antigen presentation. These results suggested that a brake to DC activation by allergens was lost following deletion of myeloid Hif1. Finally, we have found that the specific deletion of Hif1 in interstitial macrophages was indeed responsible of the observed effects. Indeed, we have shown that the TLR-dependent activation of Myd88 in interstitial macrophages induced increased expression of Hif1, thereby increasing IL-10 production from interstitial macrophages. In addition, following HDM stimulation, we observed that Hif1αm-/- interstitial macrophages produced significantly less IL-10 than control interstitial macrophages. Since we have previously shown that interstitial macrophages were capable of blocking dendritic cell activation through the production of IL-10, we proposed that Hif1 was able to control the immunoregulatory functions of interstitial macrophages by regulating their IL-10 production. Our work revealed a crucial role for Hif1 in interstitial macrophages for maintaining the immune homeostasis in the lung. It also suggests for the first time that Hif1 within innate immune cells can display an anti-inflammatory role. As a conclusion, we have been able to assess the importance of Hif1 activation within innate immune cells in the regulation of airway allergy development. We have further proposed that a compartmentalization of pro- and anti-inflammatory functions of Hif1 exists in immune cells. In opposition to what we obtained in the first study and what is currently known in the literature; we have found an anti-inflammatory role for Hif1 in innate immune cells. Indeed, thanks to its role in interstitial macrophages, Hif1 can play a crucial role in the prevention of aberrant immune responses against harmless antigens by preventing allergic sensitization. Hif1 therefore plays a key role in maintaining lung mucosal immune homeostasis. [less ▲]

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See detailResident CD11b(+)Ly6C(-) Lung Dendritic Cells Are Responsible for Allergic Airway Sensitization to House Dust Mite in Mice.
Mesnil, Claire ULg; Sabatel, Catherine ULg; Marichal, Thomas ULg et al

in PLoS ONE (2012), 7(12), 53242

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway ... [more ▼]

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to naive recipients. Transfer of lung CD11c(+)CD11b(+) DCs, but not CD11c(+)CD11b(-)CD103(+) DCs, was sufficient to prime airway allergy. The CD11c(+)CD11b(+) DC subpopulation was composed of CD11c(+)CD11b(+)Ly6C(+) inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c(+)CD11b(+)Ly6C(-) DCs, which remain stable. Counterintuitively, only CD11c(+)CD11b(+)Ly6C(-) DCs, and not CD11c(+)CD11b(+)Ly6C(+) DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c(+)CD11b(+)Ly6C(-) DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice. [less ▲]

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See detailIncreased hypoxia-inducible factor 1alpha expression in lung cells of horses with recurrent airway obstruction.
Toussaint, Marie ULg; Fievez, Laurence ULg; Desmet, Christophe ULg et al

in BMC Veterinary Research (2012), 8(1), 64

ABSTRACT: BACKGROUND: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological ... [more ▼]

ABSTRACT: BACKGROUND: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-alpha in myeloid cells in horse with recurrent airway obstruction. RESULTS: In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-alpha mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-alpha mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. CONCLUSION: Taken together, our results suggest an important role for Hif1-alpha in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO. [less ▲]

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See detailMyeloid HIF-1alpha prevents airway allergy in mice by promoting macrophage-mediated immunosuppression
Toussaint, Marie ULg; Fievez, Laurence ULg; Lekeux, Pierre ULg et al

in Proceedings of the 1st Scientific Meeting of the Faculty of Veterinary Medicine (2011, December 09)

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See detailEtude de l'administration par inhalation de cefquinome chez le cheval sain
Art, Tatiana ULg; Van Erk, E.; Ramery, Eve ULg et al

in Pratique Vétérinaire Equine (2008), 40

Cefquinome aerosol is sometimes used in horse suffering from respiratory infections. However, harmlessness and validity of the method has never been studied. This work aimed at controlling the lack of ... [more ▼]

Cefquinome aerosol is sometimes used in horse suffering from respiratory infections. However, harmlessness and validity of the method has never been studied. This work aimed at controlling the lack of pulmonary effects of cefquinome when administered through inhalation in healthy horses and at comparing the cefquinome concentrations obtained in broncho-alveolar lavage after aerosol, intramuscular and intravenous administrations. A single aerosol of cefquinome did not induce any detectable side effect in healthy horses and allowed to obtain broncho-alveolar concentrations higher than obtained with intravenous and intramuscular injection. These results should now be completed by further studies, especially on horses suffering from respiratory disease and bronchial hyperreactivity [less ▲]

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