Blockade of RGMb inhibits allergen-induced airways disease

Abstract

Background: Allergic asthma causes morbidity in many subjects, and novel precision-directed treatments would be valuable. Objective: We sought to examine the role of a novel innate molecule, repulsive guidance molecule b (RGMb), in murine models of allergic asthma. Methods: In models of allergic asthma using ovalbumin or cockroach allergen, mice were treated with anti-RGMb or control mAb and examined for airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. The mechanisms by which RGMb causes airways disease were also examined. Results: We found that blockade of RGMb by treatment with anti-RGMb mAb effectively blocked the development of airway inflammation and AHR. Importantly, blockade of RGMb completely blocked the development of airway inflammation and AHR, even if treatment occurred only during the challenge (effector) phase. IL-25 played an important role in these models of asthma because IL-25 receptor-deficient mice did not develop disease after sensitization and challenge with allergen. RGMb was expressed primarily by innate cells in the lungs, including bronchial epithelial cells (known producers of IL-25), activated eosinophils, and interstitial macrophages, which in the inflamed lung expressed the IL-25 receptor and produced IL-5 and IL-13. We also found that neogenin, the canonical receptor for RGMb, was expressed by interstitial macrophages and bronchial epithelial cells in the inflamed lung, suggesting that an innate RGMb-neogenin axis might modulate allergic asthma. Conclusions: These results demonstrate an important role for a novel innate pathway in regulating type 2 inflammation in patients with allergic asthma involving RGMb and RGMbexpressing cells, such as interstitial macrophages and bronchial epithelial cells. Moreover, targeting this previously unappreciated innate pathway might provide an important treatment option for allergic asthma. (J Allergy Clin Immunol 2019;144:94-108.)

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“…Targeting PD-L2 using its ligand, repulsive guidance molecule b (RGMb), was proposed a therapeutic approach for allergic asthma [24]. However, it has been recently revealed that the anti-allergic effect of RGMb in a mouse model of asthma is independent of PD-L2 interaction further confirmed in PD-L2 deficient mice sensitized to OVA which may require to be validated in protease allergen models such as HDM [25]. In addition, Minkyoung et al have reported a complex mechanism in which protease-fibrinogen cleavage products-TLR4-mast cell-IL-13 axis favors development of pro-allergic/asthmatic PD-L2 + DCs in mice [26].…”

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