Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation.
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.
Chora
Angelo A
AA
Instituto Gulbenkian de Ciência, Oeiras, Portugal. Departamento de Imunologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
Fontoura
Paulo
P
Cunha
Andreia
A
Pais
Teresa F
TF
Cardoso
Sílvia
S
Ho
Peggy P
PP
Lee
Lowen Y
LY
Sobel
Raymond A
RA
Steinman
Lawrence
L
Soares
Miguel P
MP
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015551:Autoimmunity; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology
D002248:Carbon Monoxide; D051547:Heme Oxygenase-1