The cytoprotective effects of leukemia inhibitory factor during bacterial pneumonia

Abstract

Pneumonia is a worldwide public health concern representing a leading burden of disease. During bacterial pneumonia, the alveolar-capillary barrier is critical for maintaining gas exchange and providing antimicrobial as well as pro-immune properties. Our group had previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, cellular targets and signaling networks required for LIF-mediated protection are unknown. Here, we found that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. LIFR is expressed on the surface of epithelial cells, and its absence elicited a significant increase in lung injury during pneumonia. Additionally, exogenous recombinant murine LIF administration into the lungs of wildtype mice had a modest but significant effect on pneumonia outcome. Finally, single-cell RNA sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing Lifr, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of Lifr. Sequencing data indicated that ATII cells were significantly impacted by pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, given relatively modest albeit significant effects of epithelial LIFR deletion, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation. To our knowledge, our findings are the first to identify cellular sources of Lifr mRNA with and without pneumonia and are also the first to demonstrate epithelial-specific consequences of LIF signaling in this context