Tuft cell–produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation

Abstract

Tuft cells produce LTC 4 and IL-25, which cooperate to promote allergen-driven airway inflammation.

Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair

“…In the trachea, i.p. administration of IL-13 was found to increase tuft cell numbers (Ualiyeva et al, 2021), and baseline tuft cell numbers were reduced in Stat6 -/- mice, with blunted response to Th2 signals (Bankova et al, 2018). In contrast to these findings which suggest that IL-13 signaling influences upper airway tuft cell differentiation, our data in distal lung indicate that IL-13 plays no role in the development of tuft cells after injury and remodeling, a somewhat surprising discrepancy given the cellular similarity between the dysplastic, “bronchiolized” Krt5 + regions and tracheal epithelium.…”

“…Aside from being induced by cytokines and leukotrienes, tuft cells also act through their production of IL-25 and LTC 4 to elicit downstream responses in the trachea and intestine. In the trachea, these tuft cell-produced inflammatory mediators synergize with each other to promote Type 2 inflammation, including eosinophil recruitment and ILC2 proliferation (Ualiyeva et al, 2021). In the small intestine, while tuft cell-produced leukotrienes are important for helminth clearance, they are dispensable for Th2 responses to protist infection (McGinty et al, 2020).…”

Brush cells fine-tune neurogenic inflammation in the airways

“…Additionally, brush cells are a dominant epithelial source of IL-25 and a key initiator of type 2 inflammation in the intestine (1,18,19) and in the airways (20,21). Brush cells from all mucosal sites also express a core set of enzymatic cascade components for cysteinyl leukotriene and prostaglandin D 2 generation, both potent proinflammatory mediators (21)(22)(23). Brush cell sensing of allergens in the airways engages an ATP-dependent feed-forward loop through the purinergic P2Y2 receptor for cysteinyl leukotriene generation (21).…”

“…Brush cells from all mucosal sites also express a core set of enzymatic cascade components for cysteinyl leukotriene and prostaglandin D 2 generation, both potent proinflammatory mediators (21)(22)(23). Brush cell sensing of allergens in the airways engages an ATP-dependent feed-forward loop through the purinergic P2Y2 receptor for cysteinyl leukotriene generation (21). In the intestine, sensing of helminth products through the succinate receptor (SUCNR1) induces cysteinyl leukotriene-and IL-25-dependent activation of innate type 2 lymphoid cells (24).…”

IL-17 Cytokines and Chronic Lung Diseases

“…IL-17E (also known as IL-25) which binds to IL-17RA/IL-17RB may have a role in the development of allergic lung disease. A recent study, for instance, suggests that IL-17E derived from tuft cells—a rare epithelial cell type—promotes type 2 inflammation in the airways [ 24 ]. The role of IL-17B and IL-17D in acute and chronic lung disease has not been studied so far.…”