Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation

Ying Cai, Geum Sil Cho, Chung Ju, Si Ling Wang, Jong Hoon Ryu, Chan Young Shin, Hee Sun Kim, Kung Woo Nam, Angela M.A. Anthony Jalin, Woong Sun, In Young Choi, Won Ki Kim

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26 Citations (Scopus)

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 ratelimiting enzyme in heme degradation in microglia. The preventive effect by LPS was significantly diminished by an iNOS inhibitor, L-N6-(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-N6-(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.

Original languageEnglish
Pages (from-to)1314-1321
Number of pages8
JournalJournal of Immunology
Volume187
Issue number3
DOIs
Publication statusPublished - 2011 Aug 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Cai, Y., Cho, G. S., Ju, C., Wang, S. L., Ryu, J. H., Shin, C. Y., Kim, H. S., Nam, K. W., Anthony Jalin, A. M. A., Sun, W., Choi, I. Y., & Kim, W. K. (2011). Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation. Journal of Immunology, 187(3), 1314-1321. https://doi.org/10.4049/jimmunol.1002925