CpG DNA-mediated induction of acute liver injury in D-galactosamine-sensitized mice: the mitochondrial apoptotic pathway-dependent death of hepatocytes.
Unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce innate inflammatory responses, including rapid induction of proinflammatory cytokines. Although innate inflammatory responses induced by CpG DNA and other pathogen-associated molecular patterns are essential for the eradication of infectious microorganisms, excessive activation of innate immunity is detrimental to the host. In this study, we demonstrate that CpG DNA, but not control non-CpG DNA, induces a fulminant liver failure with subsequent shock-mediated death by promoting massive apoptotic death of hepatocytes in D-galactosamine (D-GalN)-sensitized mice. Inhibition of mitochondrial membrane permeability transition pore opening or caspase 9 activity in vivo protects D-GalN-sensitized mice from the CpG DNA-mediated liver injury and death. CpG DNA enhanced production of proinflammatory cytokines in D-GalN-sensitized mice via a TLR9/MyD88-dependent pathway. In addition, CpG DNA failed to induce massive hepatocyte apoptosis and subsequent fulminant liver failure and death in D-GalN-sensitized mice that lack TLR9, MyD88, tumor necrosis factor (TNF)-alpha, or TNF receptor I but not interleukin-6 or -12p40. Taken together, our results provide direct evidence that CpG DNA induces a severe acute liver injury and shock-mediated death through the mitochondrial apoptotic pathway-dependent death of hepatocytes caused by an enhanced production of TNF-alpha through a TLR9/MyD88 signaling pathway in D-GalN-sensitized mice.
Children's Foundation Research Center at Le Bonheur Children's Medical Center and the Department of Pediatrics, University of Tennessee Health Science Center, 50 N. Dunlap Street, Memphis, TN 38103, USA. ayi@utmem.edu
Ae-Kyung
AK
Yi
Hyunsook
H
Yoon
Jeoung-Eun
JE
Park
Beom-Sue
BS
Kim
Hae Jong
HJ
Kim
Antonio
A
Martinez-Hernandez
D000818:Animals; D017209:Apoptosis; D018899:CpG Islands; D004247:DNA / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005688:Galactosamine / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism*; D007249:Inflammation; D008099:Liver / Q000293:injuries*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005688:Galactosamine; D004247:DNA