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Respiratory Airway Secretory Cells act as Immune Sentinels in Human Distal Airways

Sun, J.; Sun, H.; Jiang, S.; Xie, X.; Wang, D.; Yao, H.; Guan, W.; Zhao, J.; Zhang, W. K.; Xu, T.; Liu, H.

2025-03-25 cell biology
10.1101/2025.03.24.644887 bioRxiv
Show abstract

Pulmonary immunity in the human distal respiratory airways is essential for lung function but remains less explored. Here we report that respiratory airway secretory (RAS) cells, a newly identified lung epithelial population unique to humans and large mammals, act as immune sentinels in the distal airways by safeguarding against infection and injury. Leveraging human pluripotent stem cell-derived lung organoids, animal models, and clinical specimens, we elucidate that RAS cells arise from distal lung progenitors and exhibit context-dependent immune competence. Upon viral or bacterial challenge, RAS cells display interferon-mediated or TLR5-dependent defense responses, respectively. In chronic obstructive pulmonary disease, they produce elevated adaptive immune responses. Notably, complement C3 is upregulated under these conditions and is suppressed by a selective TLR5 inhibitor. Our findings reveal RAS cells as previously unrecognized sensors and effectors of mucosal immunity at human distal airways, highlighting the TLR5-complement axis as a potential therapeutic target in lung disease.

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