Journal Article

Pulmonary fibroblast-derived stem cell factor promotes neutrophilic asthma by augmenting IL-17A production from ILC3s

Lai, Alan Chuan-Ying, Chang, Yao-Ming, Chi, Po-Yu, Chang, Ya-Jen, Shao, Jheng-Syuan, Huang, Wei-Chang, Wu, Ko-Chien

2025

Overview

Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in the lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in the lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor c-Kit reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in the lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.

• Publisher: American Society for Clinical Investigation
• Subject: Air pollution / AKT protein / Analysis / Animals / Asthma / Asthma - genetics / Asthma - immunology / Asthma - metabolism / Asthma - pathology / B cells / c-Kit protein / Cell activation / Cytokines / Female / Fibroblasts / Fibroblasts - immunology / Fibroblasts - metabolism / Fibroblasts - pathology / Genes / Helper cells / Humans / Imatinib / Immunity, Innate / Immunology / Inflammation / Interleukin-17 - biosynthesis / Interleukin-17 - genetics / Interleukin-17 - immunology / Leukocytes (neutrophilic) / Lipopolysaccharides / Lung - immunology / Lung - metabolism / Lung - pathology / Lymphocytes / Lymphocytes - immunology / Lymphocytes - metabolism / Lymphocytes - pathology / Lymphocytes T / Lymphoid cells / Male / Mice / Mice, Knockout / Neutrophils / Neutrophils - immunology / Neutrophils - pathology / Ovalbumin / Stat3 protein / Stem cell factor / Stem Cell Factor - genetics / Stem Cell Factor - immunology / Stem Cell Factor - metabolism / Stem cells / Therapeutic targets / Transcriptomics