Asthma and beta2-adrenergic receptor – Asthmatreat

- Production and characterization of transgenic mice in which regulatory T cells are selectively deficient in the expression of the ß2 adrenergic receptor
- Production and characterization of transgenic mice in which airway epithelial cells are selectively deficient in the expression of the ß2 adrenergic receptor
- Production and characterization of transgenic mice in which airway muscular cells are selectively deficient in the expression of the ß2 adrenergic receptor
- Single cell transcriptomic analysis of epithelial cells at the air-liquid interface.

- The expression of the ß2 adrenergic receptor by T cells does not play a role in the development of allergic asthma at least in mcie. Therefore, regulatory T cells are not the targets of ß2 adrenergic receptor antagonists in experiments in which these molecules are used to inhibit allergen-induced asthma in mice.

To complete our experiments aimed at investigating the role of the ß2 adrenergic receptor in airway epithelial and muscle cells.

1. Trian T, et coll. 2015. Am J Respir Crit Care Med 191: 538-46
2. Girodet PO, et coll.. 2015. Am J Respir Crit Care Med 191: 876-83
3. Fayon M, et coll.. 2015. . PLoS One 10: e0122446
4. Girodet PO, et coll.. 2016. Am J Respir Crit Care Med 193: 627-33
5. Dupin I, et coll.. 2016. J Allergy Clin Immunol 137: 1036-42 e1-7
6. Navarro S, Pickering DA, Ferreira IB, Jones L, Ryan S, Troy S, Leech A, Hotez PJ, Zhan B, Laha T, Prentice R, Sparwasser T, Croese J, Engwerda CR, Upham JW, Julia V, Giacomin PR, Loukas A. 2016. . Sci Transl Med 8: 362ra143
7. Julia V, Staumont-Salle D, Dombrowicz D. 2016. Med Sci (Paris) 32: 260-6
8. Kanda A, Fleury S, Kobayashi Y, Tomoda K, Julia V, Dombrowicz D. 2015. . Allergol Int 64 Suppl: S71-3
9. Julia V, Macia L, Dombrowicz D. 2015. Nat Rev Immunol 15: 308-22
10. Navarro S, Lazzari A, Kanda A, Fleury S, Dombrowicz D, Glaichenhaus N, Julia V. 2015. . Mucosal Immunol 8: 841-51
11. Staumont-Salle D, Fleury S, Lazzari A, Molendi-Coste O, Hornez N, Lavogiez C, Kanda A, Wartelle J, Fries A, Pennino D, Mionnet C, Prawitt J, Bouchaert E, Delaporte E, Glaichenhaus N, Staels B, Julia V, Dombrowicz D. 2014. J Exp Med 211: 1185-96
12. Navarro S, Lazzari A, Kanda A, Fleury S, Dombrowicz D, Glaichenhaus N, Julia V. 2015. Mucosal Immunol 8: 841-51
13. Arguel MJ, LeBrigand K, Paquet A, Ruiz Garcia S, Zaragosi LE, Barbry P, Waldmann R. 2016. Nucleic Acids Res
14. Beclin C, Follert P, Stappers E, Barral S, Nathalie C, de Chevigny A, Magnone V, Lebrigand K, Bissels U, Huylebroeck D, Bosio A, Barbry P, Seuntjens E, Cremer H. 2016. . Sci Rep 6: 35729
15. Popa A, Lebrigand K, Paquet A, Nottet N, Robbe-Sermesant K, Waldmann R, Barbry P. 2016. F1000Res 5: 1309
16. Barbry P, Zaragosi LE. 2014. An ABC of ciliogenesis. Nat Cell Biol 16: 826-7
17. Cibois M, Luxardi G, Chevalier B, Thome V, Mercey O, Zaragosi LE, Barbry P, Pasini A, Marcet B, Kodjabachian L. 2015. Development 142: 2352-63

Asthma is a complex chronic inflammatory disease of the lungs characterized by airflow obstruction, airway hyper responsiveness (AHR) and airway inflammation. Inflammation and intermittent constriction of the airways give rise to symptoms of wheeze, cough, chest tightness and shortness of breath. Chronic disease leads to structural changes termed airway remodeling that may result in irreversible airway limitation. Because of their potent broncho-dilating effects, short-acting agonists of the beta2-adrenoreceptor (beta2-AR) are the standard treatment for the acute relief of asthma. Long-acting beta2-AR agonists are traditionally given as add-on therapies to inhaled corticosteroids for maintenance therapy of moderate and severe asthma. However, the chronic administration of long-acting or short-acting beta2-AR agonists has been associated with tolerance, increased AHR to allergen, poor asthma control, and death. Surprisingly, recent pharmacological and genetic evidence in mice and clinical data in humans have shown that constitutive signaling through beta2-AR is required for the full development of asthma. As compared to wild-type (wt) mice, beta2-AR-deficient mice exhibited reduced AHR, airway inflammation and mucous metaplasia upon sensitization and challenge with ovalbumin (OVA). Most importantly, the chronic administration of the inverse beta-AR agonist, nadolol, to patients with mild asthma induced a dose-dependent decrease in AHR. Although these findings may appear paradoxical in view of the fact that chronic activation of the beta2-AR has long been thought to be beneficial in asthma, they may cause a paradigm shift in the future pharmacological management of chronic asthma.

Despite recent studies showing that constitutive signaling through beta2-AR is required for the full development of asthma, it remains to be determined which cell types are involved in beta2-AR-dependent allergic inflammation and how beta2-AR signaling impacts molecular and cellular interactions during disease progression. As a first step to identify the cell types that are involved in ß2-AR-dependent allergic inflammation, we will use a combination of pharmacological and genetic approaches to determine whether beta2-AR exhibits constitutive signaling activity in airway smooth muscle (ASM) cells, airway epithelial cells, and regulatory T cells (Treg). Next, we will investigate whether airway allergic inflammation in mice requires the expression of beta2-AR on hematopoietic cells, non-hematopoietic cells, or both. To this aim, we will generate and analyze bone marrow chimeras in which cells from these compartments are selectively deficient in beta2-AR. To unambiguously identify the cell types that are required for beta2-AR-dependent allergic inflammation, we will use the Cre/loxP technology to generate mice in which ASM cells, airway epithelial cells, or Treg will be selectively deficient in beta2-AR. These mice will be sensitized and challenged with OVA or Dermatophagoides pteronyssinus (D.pter) and characterized from cardinal features of asthma including AHR, eosinophilia, high levels of serum IgE and the presence of IL-4, IL-5 and IL-13 in the lungs, and airway remodeling. Results generated during this project may lead to the design of new pharmaceutical targets and therapeutic strategies to improve asthma management.