Interleukin-17 is a negative regulator of established allergic asthma.
T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R-deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)-the major source of TARC-and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4-dependent manner since mice deficient for IL-4Ralpha signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis.
Schnyder-Candrian
Silvia
S
Université d' Orléans, Centre national de la Recherche Scientifique (CNRS), Molecular Immunology and Embryology, 45071 Orléans, France.
Togbe
Dieudonnée
D
Couillin
Isabelle
I
Mercier
Isabelle
I
Brombacher
Frank
F
Quesniaux
Valérie
V
Fossiez
Francois
F
Ryffel
Bernhard
B
Schnyder
Bruno
B
D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D054413:Chemokine CCL11; D054414:Chemokine CCL17; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage
D000485:Allergens; C515457:Ccl11 protein, mouse; C499538:Ccl17 protein, mouse; D054413:Chemokine CCL11; D054414:Chemokine CCL17; D018946:Chemokine CCL5; D019742:Chemokines, CC; D020381:Interleukin-17; D010047:Ovalbumin