Tracheal tuft cell-released leukotrienes promote antibacterial immune responses

SUMMARY Tuft cells act as crucial sentinels in the airways that detect bacterial metabolites. In response, tuft cells release signaling molecules that trigger immune responses essential for clearing the infection. The molecular mechanisms driving immune cell activation following tuft cell stimulation in pneumonia are still not fully understood. Here, we identify tuft cells as the primary source of proinflammatory leukotrienes (LTs), which are released in the presence of pathogenic bacteria in the airways. We show that tracheal tuft cells discriminate pathogenic from non-pathogenic bacteria by sensing adenosine triphosphate (ATP) released from pathogens such as Pseudomonas aeruginosa and Rodentibacter pneumotropicus within the first 4 h of invasion, and recruit neutrophils and macrophages to the trachea and alveolar spaces. Taste signaling through the chemosensory transient receptor potential cation channel subfamily M member 5 (Trpm5) channel was essential for tuft cell activation and LT release. Mice lacking Trpm5 were not capable of detecting bacteria-released ATP and became colonized upon R. pneumotropicus infection. In contrast, Trpm5+/+ mice cleared the pathogen. We uncover a critical tuft cell-dependent sensing mechanism in pneumonia and establish tracheal tuft cells as both detectors of bacterial extracellular ATP and triggers of acute innate immune responses.