Etude du rôle de l’Hypoxia Inductible Facteur 1 dans les cellules myéloïdes lors d'allergie des voies respiratoires

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.