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Objective <p>Toll-interacting protein (Tollip) suppresses excessive pro-inflammatory signaling, but its function in airway epithelial responses to IL-13, a key mediator in allergic diseases, remains unclear. This study investigates Tollip knockdown (TKD) effects in primary human airway epithelial cells using single-cell RNA sequencing, providing the first single-cell analysis of TKD and the first exploring its interaction with IL-13.</p> Results <p>IL-13 treatment upregulated key genes, including SPDEF, MUC5AC, POSTN, ALOX15, and CCL26, confirming IL-13’s effects and validating our methods. IL-13 reduced TNF-α signaling and epithelial-mesenchymal transition in certain cell types, suggesting a dual role in promoting type 2 inflammation while suppressing Th1-driven inflammation. Tollip deficiency alone significantly amplified TNF-α signaling and inflammatory pathways in goblet, club, and suprabasal cells. Comparisons between TKDIL13 vs IL13 and TKD vs CTR revealed that IL-13 does not substantially alter Tollip deficiency response in most cell types, reinforcing findings in TKD vs CTR. Tollip deficiency alters the response to IL-13 in a cell-type-specific manner, strongly downregulating TNF-α signaling in goblet cells but only weakly in basal and club cells. Tollip deficiency enhances IL-13’s suppression of Th1 inflammatory responses in goblet cells. These novel insights in Tollip-IL-13 interactions offer potential therapeutic targets for asthma and related diseases.</p>

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Comprehensive single-cell RNA-sequencing study of Tollip deficiency effect in IL-13-stimulated human airway epithelial cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月23日

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  • Grace Yihua Lee,
  • Niccolette Schaunaman,
  • Hamid Reza Nouri,
  • Monica Kraft,
  • Hong Wei Chu

摘要

Objective

Toll-interacting protein (Tollip) suppresses excessive pro-inflammatory signaling, but its function in airway epithelial responses to IL-13, a key mediator in allergic diseases, remains unclear. This study investigates Tollip knockdown (TKD) effects in primary human airway epithelial cells using single-cell RNA sequencing, providing the first single-cell analysis of TKD and the first exploring its interaction with IL-13.

Results

IL-13 treatment upregulated key genes, including SPDEF, MUC5AC, POSTN, ALOX15, and CCL26, confirming IL-13’s effects and validating our methods. IL-13 reduced TNF-α signaling and epithelial-mesenchymal transition in certain cell types, suggesting a dual role in promoting type 2 inflammation while suppressing Th1-driven inflammation. Tollip deficiency alone significantly amplified TNF-α signaling and inflammatory pathways in goblet, club, and suprabasal cells. Comparisons between TKDIL13 vs IL13 and TKD vs CTR revealed that IL-13 does not substantially alter Tollip deficiency response in most cell types, reinforcing findings in TKD vs CTR. Tollip deficiency alters the response to IL-13 in a cell-type-specific manner, strongly downregulating TNF-α signaling in goblet cells but only weakly in basal and club cells. Tollip deficiency enhances IL-13’s suppression of Th1 inflammatory responses in goblet cells. These novel insights in Tollip-IL-13 interactions offer potential therapeutic targets for asthma and related diseases.