TLR9 signaling delays neutrophil apoptosis by increasing transcription of Mcl‐1

Delayed neutrophil apoptosis aggravates and prolongs the inflammatory response. Bacterial DNA (CpG DNA) can retard neutrophil apoptosis via increases in the cellular levels of Mcl‐1, an anti‐apoptotic protein with a rapid turnover rate. We investigated whether bacterial DNA could enhance neutrophil longevity by altering the rate of Mcl‐1 turnover. Culture of human isolated neutrophils with CpG DNA resulted in concurrent activation of the ERK and PI3‐kinase/Akt signaling pathways, prevention of Mcl‐1 degradation and suppression of apoptosis, which was blocked by the telomere‐derived oligonucleotide TTAGGG. In contrast to granulocyte macrophage colony‐stimulating factor, CpG DNA exerted only a slight inhibitory effect on proteosomal degradation of Mcl‐1. CpG DNA markedly enhanced NF‐kB‐mediated Mcl‐1 transcription and Mcl‐1 translocation from the cytoplasm to the mitochondria. Our results indicate that CpG DNA suppression of neutrophil apoptosis occurs via changes in Mcl‐1 turnover predominantly due to enhanced Mcl‐1 gene transcription, and support that CpG DNA could contribute to prolongation and amplification of inflammation. (Grant support: CIHR MOP‐97742).