Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation

J Clin Invest. 2007 Feb;117(2):438-47. doi: 10.1172/JCI28844. Epub 2007 Jan 25.

Abstract

Heme oxygenase-1 (HO-1, encoded by HMOX1) dampens inflammatory reactions via the catabolism of heme into CO, Fe, and biliverdin. We report that expression of HO-1 dictates the pathologic outcome of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Induction of EAE in Hmox1(-/- )C57BL/6 mice led to enhanced CNS demyelination, paralysis, and mortality, as compared with Hmox1(+/+) mice. Induction of HO-1 by cobalt protoporphyrin IX (CoPPIX) administration after EAE onset reversed paralysis in C57BL/6 and SJL/J mice and disease relapse in SJL/J mice. These effects were not observed using zinc protoporphyrin IX, which does not induce HO-1. CoPPIX protection was abrogated in Hmox1(-/-) C57BL/6 mice, indicating that CoPPIX acts via HO-1 to suppress EAE progression. The protective effect of HO-1 was associated with inhibition of MHC class II expression by APCs and inhibition of Th and CD8 T cell accumulation, proliferation, and effector function within the CNS. Exogenous CO mimicked these effects, suggesting that CO contributes to the protective action of HO-1. In conclusion, HO-1 or exposure to its end product CO counters autoimmune neuroinflammation and thus might be used therapeutically to treat MS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Autoimmunity
  • Carbon Monoxide / metabolism
  • Carbon Monoxide / pharmacology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Enzyme Induction
  • Heme Oxygenase-1 / deficiency
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocyte Subsets / immunology

Substances

  • Carbon Monoxide
  • Heme Oxygenase-1