GDNF-RET signaling drives pulmonary neuroendocrine cell hyperplasia and allergic airway inflammation

Pulmonary neuroendocrine cell (PNEC) hyperplasia often occurs in lung diseases, including allergic asthma. We previously reported that PNEC-derived calcitonin gene-related peptide (CGRP) likely stimulates group 2 innate lymphoid cells (ILC2), exacerbating asthma phenotypes in a mouse model. Here, we investigate the role of glial cell-line derived neurotrophic factor (GDNF) and rearranged during transfection (RET) signaling in PNEC hyperplasia and its therapeutic potential in asthma. PNECs expressed GDNF receptors, which were activated primarily by infiltrating inflammatory cells. Application of a RET-specific inhibitor suppressed ILC2 levels, PNEC hyperplasia and airway allergic responses. We suggest that GDNF-RET signaling promotes PNEC hyperplasia and that the PNEC-CGRP-ILC2 axis is closely associated with the development of allergic asthma, presenting a possible new treatment strategy. Impact statement Our study is the first to indicate the possibility of controlling pulmonary neuroendocrine cell (PNEC) hyperplasia and acute allergic airway inflammation through RET signaling, which could lead to elucidating the mechanism underlying the PNEC hyperplasia-immune relationship in asthma. We propose that targeting this could be a new treatment strategy.