[New paradigm of host defense against intracellular pathogens by nitric oxide].
Nitric oxide (NO) produced by inducible NO synthase (iNOS) during infection plays a crucial role in host defense mechanisms, via its antimicrobial and cytoprotective activities. Infection of Salmonella typhimurium in mice induces excessive production of NO, as a host defense response. We found much greater bacterial growth and apoptotic changes in iNOS-deficient (iNOS-/-) mice than in wild-type mice. However, the mechanism of NO-mediated cytoprotection during Salmonella infection remained unclear. An important signaling mechanism induced by NO is heme oxygenase (HO)-1, a significant cytoprotective molecule produced by oxidative stress. Thus, we sought to clarify NO-dependent cytoprotective and antimicrobial host defense, with a particular focus on the signaling mechanism of HO-1 induction. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via NO possibly with reactive oxygen species. We observed strong immunoreactivity for 8-nitro-cGMP in Salmonella-infected wild-type mouse liver and peritoneal macrophages in culture but not in iNOS-/- mouse liver and macrophages. Moreover, a higher apoptosis was observed in iNOS-/- macrophages compared with wild-type macrophages after Salmonella infection, but the difference was nullified when iNOS-/- cells were treated with 8-nitro-cGMP. Finally, authentic 8-nitro-cGMP induced HO-1 in cultured macrophages infected with Salmonella. The signaling function of 8-nitro-cGMP appears to be mediated by its unique reaction with the sulfhydryl group of cysteine, thus forming a proteinS-cGMP adduct, which is an important mechanism of post-translational modification of proteins called protein S-guanylation. More importantly, we found 8-nitro-cGMP-dependent S-guanylation of Keap1, a regulatory protein of transcription factor Nrf2, which regulates the transcription of HO-1. In this review, we focus on a unique mechanism of NO-mediated host defense via formation of a novel signaling molecule, 8-nitro-cGMP in microbial infections.
Akaike
Takaaki
T
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. takakaik@gpo.kumamoto-u.ac.jp
Okamoto
Tatsuya
T
Zaki
Md Hasan
MH
Fujii
Shigemoto
S
Sawa
Tomohiro
T
D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D019610:Cytoprotection; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D012480:Salmonella Infections; D015398:Signal Transduction / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology
C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D006152:Cyclic GMP