Abstract
Neutrophils are required for host resistance against Streptococcus pneumoniae but their function declines with age. We previously found that CD73, an enzyme required for antimicrobial activity, is down-regulated in neutrophils from aged mice. This study explored transcriptional changes in neutrophils induced by S. pneumoniae to identify pathways controlled by CD73 and dysregulated with age. Ultrapure bone marrow-derived neutrophils isolated from wild type (WT) young, old, and CD73KO young mice were mock-challenged or infected with S. pneumoniae ex vivo. RNA sequencing was performed to identify differentially expressed genes (DEGs). We found that infection triggered distinct global transcriptional changes across hosts, that were strongest in CD73KO neutrophils. Surprisingly, there were more down-regulated than up-regulated genes in all groups upon infection. Down-regulated DEGs indicated a dampening of immune responses in old and CD73KO hosts. Further analysis revealed that CD73KO neutrophils expressed higher numbers of long non-coding RNAs (lncRNAs) compared to WT controls. Predicted network analysis indicated that CD73KO specific lncRNAs control several signaling pathways. We found that genes in the JNK-MAPK-pathway were up-regulated upon infection in CD73KO and WT old but not in young mice. This corresponded to functional differences, as phosphorylation of the downstream AP-1 transcription factor component c-Jun was significantly higher in infected CD73KO and old mice neutrophils. Importantly, inhibiting JNK/AP-1 rescued the ability of these neutrophils to kill S. pneumoniae. Altogether, our findings revealed that neutrophils modify their gene expression to better adapt to bacterial infection and that this capacity declines with age and is regulated by CD73.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest: The authors have declared that no conflict of interest exists
↵1 This work supported by National Institute of Health grant R00AG051784 and a University at Buffalo Clinical and Translational Science Institute pilot award CTSA1153519 to ENBG. OBM was supported by an American Association of Immunologists Careers in Immunology fellowship and a College of Health Sciences and Technology bridge grant.
↵2 Elsa N. Bou Ghanem, 955 Main Street, Buffalo, NY, 14203. Telephone: 716-829-2422. Email: elsaboug{at}buffalo.edu
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE150811