Pulmonary fibroblast-derived stem cell factor promotes neutrophilic asthma by augmenting IL-17A production from ILC3s
Jheng-Syuan Shao, Alan Chuan-Ying Lai, Wei-Chang Huang, Ko-Chien Wu, Po-Yu Chi, Yao-Ming Chang, Ya-Jen Chang
Jheng-Syuan Shao, Alan Chuan-Ying Lai, Wei-Chang Huang, Ko-Chien Wu, Po-Yu Chi, Yao-Ming Chang, Ya-Jen Chang
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Research Article Immunology Inflammation

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

Abstract

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.

Authors

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

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Figure 1

SCF expression correlates to IL-17A and MPO in asthmatic patients and synergizes with IL-1β/IL-23 to enhance ILC3 responses and neutrophilic inflammation in mouse model.

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SCF expression correlates to IL-17A and MPO in asthmatic patients and sy...
(A) Protein levels of SCF and IgE in the plasma of Type 2 and non-Type 2 asthmatic patients and healthy controls. n = 7–11 per group. (B) U-BIOPRED blood gene expression for KITLG by severity cohort. Correlation between KITLG and IL17A gene expression in blood. (Pearson correlation, dotted line represents 95% CI) Data was obtained from GSE69683. n = 498 for healthy, moderate, and severe asthma. (C and D) U-BIOPRED induced sputum gene expression. Data was obtained from GSE76262. n = 139 for healthy, moderate, and severe asthma. (C) Gene expression for KITLG by severity cohort. Correlation between KITLG and IL17A gene expression in sputum. (Pearson correlation, dotted line represents 95% CI). (D) Correlation between KITLG and MPO gene expression in sputum. (Pearson correlation, dotted line represents 95% CI). (E and F) scRNA-seq of human lung T cells and ILCs. Data was obtained from the Human Cell Atlas. (E) Uniform Manifold Approximation and Projection (UMAP) plots of human lung T cells and ILCs and feature plots showing enrichment of KIT to cell clusters. (F) Dot plot for KIT expression of cell clusters. (G) Representative histograms of c-Kit expression in lung ILC3 (CD45+Thy1.2+Lin-ROR-γt+), γδT (CD45+Thy1.2+γδTCR+) and T cells (CD45+Thy1.2+Lin+γδTCR-) from C57BL/6 (WT) mice. (H–M) C57BL/6 (WT) mice intranasally (i.n.) received IL-1β/IL-23 and/or SCF for 3 days (Days 0–2) and were sacrificed on day 6 for following analysis. (H) Flow cytometry analysis of ILC3s. (I) Numbers of lung ILC3s (CD45+Thy1.2+Lin-ROR-γt+) and IL-17A+ ILC3s (CD45+Thy1.2+Lin-ROR-γt+IL-17A+). (J) Representative histograms of ROR-γt expression. (K) MFI of ROR-γt in lung ILC3s. (L) mRNA levels of Il17a in lung lysates. (M) Numbers of neutrophils (NEU) in BALF. n = 5–6 per group. Data are mean ± SEM and are representative of at least 2 independent experiments. Significance was determined by 1-way ANOVA (A–C, I, and K–M).