Yujiao Xiang, Jielu Liu, Ionut Atanasoai, Rana Seren, Jesper Säfholm, Yitao Gong, Sofia Mogren, Celsia E Bosewel, Anna-Karin Jonsson, Sachin K Samuchiwal, Mu Nie, Elin Rönnberg Höckerlind, Cecilia Andersson, Craig E Wheelock, Michael J Turner, Gunnar Nilsson, Mikael Adner
Mast cell-dependent signaling is a key driver of allergic asthma pathogenesis. Pharmacological inhibition of KIT effectively suppresses mast cell activity and prevents hallmark functional and structural features of asthma in a guinea pig model, supporting KIT inhibition as a potential therapeutic approach for allergic asthma.
BACKGROUND: Asthma is a chronic respiratory disease characterized by airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. Mast cell numbers are increased in asthmatic airways and contribute to bronchoconstriction and inflammation; yet their role in asthma development remains elusive.
OBJECTIVE: To investigate mast cell contributions to allergic asthma by pharmacologically targeting KIT, a central regulator of mast cell survival and activation, using the selective inhibitor THB001.
METHODS: THB001 effects were assessed in human lung mast cells (HLMCs), isolated human bronchi, and guinea pig trachea. To probe mast cell contributions in vivo, guinea pigs were subjected to a house dust mite (HDM)-induced asthma model and treated with THB001. HDM-induced bronchoconstriction was recorded after each challenge. At the endpoint, airway responsiveness was evaluated, followed by bronchoalveolar lavage fluid and lung tissue collection for histological, biochemical and transcriptomic analyses.
RESULTS: THB001 suppressed KIT-dependent mast cell functions, inhibiting HLMCs degranulation and survival, and attenuating anti-IgE-induced bronchial contraction. In guinea pig tracheal segments, THB001 reduced HDM-induced responses, coinciding with a reduction in mast cells. In vivo, THB001 remodeled HDM-induced transcriptional signatures and lipid mediator release, prevented HDM-induced bronchoconstriction and AHR, and largely reversed HDM-induced increases in mast cells, inflammation, airway smooth muscle layer thickening and collagen deposition, with partial reduction of mucus-producing cells.
CONCLUSIONS: Mast cell-dependent signaling is a key driver of allergic asthma pathogenesis. Pharmacological inhibition of KIT effectively suppresses mast cell activity and prevents hallmark functional and structural features of asthma in a guinea pig model, supporting KIT inhibition as a potential therapeutic approach for allergic asthma.