| First Author | Ualiyeva S | Year | 2021 |
| Journal | Sci Immunol | Volume | 6 |
| Issue | 66 | Pages | eabj0474 |
| PubMed ID | 34932383 | Mgi Jnum | J:338728 |
| Mgi Id | MGI:7514471 | Doi | 10.1126/sciimmunol.abj0474 |
| Citation | Ualiyeva S, et al. (2021) Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation. Sci Immunol 6(66):eabj0474 |
| abstractText | Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25 (IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not been clarified. Here, we showed that inhalation of the parent leukotriene C(4) (LTC(4)) in combination with a subthreshold dose of IL-25 led to activation of two innate immune cells: inflammatory type 2 innate lymphoid cell (ILC2) for proliferation and cytokine production, and dendritic cells (DCs). This cooperative effect led to a much greater recruitment of eosinophils and CD4(+) T cell expansion indicative of synergy. Whereas lung eosinophilia was dominantly mediated through the classical CysLT receptor CysLT(1)R, type 2 cytokines and activation of innate immune cells required signaling through CysLT(1)R and partially CysLT(2)R. Tuft cell-specific deletion of Ltc4s, the terminal enzyme required for CysLT production, reduced lung inflammation and the systemic immune response after inhalation of the mold aeroallergen Alternaria; this effect was further enhanced by concomitant blockade of IL-25. Our findings identified a potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs. |
