Blockade of the Neogenin-RGMb-BMP signaling hub inhibits allergen-induced airway hyperreactivity

Bronchial asthma is associated with type 2 immune responses induced by components of adaptive as well as innate immunity. Although innate cytokines such as IL-25 have been shown to play a key role in development of airway hyperreactivity (AHR), little is known of innate molecules that regulate IL-25-mediated airway inflammation. We found that blockade of repulsive guidance molecule b (RGMb) in an experimental murine model of asthma blocked the development of AHR, a cardinal feature of asthma, and that RGMb is expressed on F4/80 + CD11b + CD11c neg macrophages (RGMb + macrophages), which accumulated in the lungs of OVA-sensitized and challenged mice, but not in naive mice. Moreover, we found that a large fraction of the RGMb + macrophages expressed the IL-25 receptor, IL-17RB, and produced IL-13. IL-25 was critical for the development of AHR in our model, since mice deficient in IL-17RB did not develop AHR. Finally, treatment with anti-RGMb mAb during the challenge phase of the protocol after allergen sensitization effectively prevented the development of AHR and airway inflammation, suggesting for the first time that RGMb + cells, including RGMb + macrophages, play critical roles in allergen-induced asthma.