Abstract The lung epithelium constitutes the first line of defense against microbial infection in the lungs. Hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor responding to cellular oxygen stress, is important for promoting expression of innate immune effectors. We found that treating lung epithelial surfaces by inhalation with the prolyl-hydroxylase domain (PHD) inhibitor vadadustat stabilizes HIF-1α, resulting in activation of HIF-1α-dependent signaling that protects against Pseudomonas pneumonia in mice. We previously reported that treatment with CpG oligodeoxynucleotides (ODN) protects against Pseudomonas pneumonia in mice, and that ODN treatment blocks mitochondrial nucleotide transition, alters cellular ATP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential, differentially modulates ETC complex activities and consequently results in formation of mitochondrial reactive oxygen species. However, whether these ODN-induced metabolic changes directly stimulate antimicrobial responses was not clear. We found that ODN treatment can stabilize HIF-1α in lung epithelium, and that the stabilized HIF-1α promotes a temporal metabolic shift to aerobic glycolysis to supplement cytosolic ATP needs after blockade of mitochondrial ATP transportation by ODN in lung epithelial cells. We demonstrated that HIF-1α activation up-regulates gene expression of antimicrobial peptides on lung epithelial surfaces and prevents bacterial invasion in the lung. These data indicate that induction of antimicrobial HIF-1α signaling contributes to ODN inducible resistance. This finding offers insights for rational design of alternate strategies to protect against fatal lung infection in patients with impaired immunity. This abstract is funded by: NIH
Wang et al. (Fri,) studied this question.