title: Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation.
abstract: In intracerebral hemorrhage, microglia become rapidly activated and remove the deposited blood and cellular debris. To survive in a harmful hemorrhagic or posthemorrhagic condition, activated microglia must be equipped with appropriate self-defensive mechanism(s) to resist the toxicity of hemin, a component released from damaged RBCs. In the current study, we found that activation of microglia by pretreatment with LPS markedly reduced their vulnerability to hemin toxicity in vitro. Similarly, intracorpus callosum microinjection of LPS prior to hemin treatment reduced the brain tissue damage caused by hemin and increased microglial density in the penumbra in rats. LPS induced the expressions of inducible NO synthase (iNOS) and heme oxygenase (HO)-1, the rate-limiting enzyme in heme degradation in microglia. The preventive effect by LPS was significantly diminished by an iNOS inhibitor, L-N(6)-(1-iminoethyl)lysine, whereas it was mimicked by a NO donor, diethylamine-NONOate, both suggesting the crucial role of NO in the modulation of hemin-induced toxicity in activated microglia. We further found that NO reduced hemin toxicity via inhibition of hemin-induced activation of JNK and p38 MAPK pathways in microglia. Whereas HO-1 expression in LPS-stimulated microglia was markedly blocked by L-N(6)-(1-iminoethyl)lysine, the HO-1 inhibitor, tin protoporphyrin, increased iNOS expression and decreased the susceptibility of LPS-activated microglia to hemin toxicity. The data indicate that the mutual interaction between NO and HO-1 plays a critical role in modulating the adaptive response of activated microglia to hemin toxicity. Better understanding of the survival mechanism of activated microglia may provide a therapeutic strategy to attenuate the devastating intracerebral hemorrhagic injury.
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.forename: Geum-Sil
authors.initials: GS
authors.lastname: Cho
authors.forename: Chung
authors.initials: C
authors.lastname: Ju
authors.forename: Si-Ling
authors.initials: SL
authors.lastname: Wang
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Kung-Woo
authors.initials: KW
authors.lastname: Nam
authors.forename: Angela M A Anthony
authors.initials: AM
authors.lastname: Jalin
authors.forename: Woong
authors.initials: W
authors.lastname: Sun
authors.forename: In-Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D006427:Hemin / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008845:Microinjections; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D009569:Nitric Oxide; D006427:Hemin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases