The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression.
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Supporting data and methods are presented in the supplementary materials. We thank X. Ai, T, Gomez, and E. Chapman for discussion; N. Hernandez-Santos for immune analysis; L. Ma, M. Tessier-Lavigne, J. Johnson, L. Wadiche, M. Zylka, and Mutant Mouse Regional Resource Center for mouse strains; and A. Lashua for technical support. This work was supported by American Heart Association predoctoral fellowship 14PRE20490146 and NIH predoctoral training grant T32 GM007133 (to K.B.), NIAID postdoctoral fellowship 5T32AI007635 (to L.N.), and NHLBI RO1 HL113870, HL097134, HL122406, University of Wisconsin Romnes Faculty Fellowship, and Wisconsin Partnership Program grant 2897 (to X.S.).