Academia Sinica Logo

Group 3 innate lymphoid cells (ILC3s) have emerged as key contributors to the pathogenesis of neutrophilic asthma, a corticosteroid-resistant asthma endotype. However, the upstream regulatory mechanisms governing pulmonary ILC3 function remain poorly understood. In this study, we identify the stem cell factor (SCF)/c-Kit signaling axis as a critical modulator of ILC3-driven airway inflammation. SCF expression was significantly upregulated in asthmatic patients and positively correlated with IL-17A and myeloperoxidase (MPO) levels, implicating a role in neutrophilic inflammation. Among pulmonary immune subsets, ILC3s were identified as major IL-17A-producing responders to SCF. In murine models, SCF synergized with IL-1β and IL-23 to enhance ILC3 activation, proliferation, and cytokine production, leading to exacerbated neutrophilic inflammation. Transcriptomic profiling of SCF-stimulated ILC3s revealed upregulation of gene programs associated with cell proliferation and Th17-like responses, accompanied by enhanced AKT and STAT3 pathway activation. Conversely, genetic ablation of c-Kit in ILC3s impaired their proliferative capacity and IL-17A secretion, attenuating AHR and airway neutrophilia. Using conditional fibroblast-specific SCF knockout mice, we further identified lung fibroblasts as the predominant source of SCF driving ILC3 responses. Therapeutically, pharmacologic inhibition of c-Kit with imatinib significantly reduced AHR and neutrophilic inflammation in multiple murine models of asthma, including those induced by IL-1β/IL-23, air pollution (PM2.5), or OVA/LPS challenge. Together, these findings uncover a previously unrecognized fibroblast–ILC3 axis regulated by SCF/c-Kit signaling, and highlight this pathway as a promising therapeutic target in neutrophilic asthma.