Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation
Ângelo A. Chora, … , Lawrence Steinman, Miguel P. Soares
Ângelo A. Chora, … , Lawrence Steinman, Miguel P. Soares
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):438-447. https://doi.org/10.1172/JCI28844.
View: Text | PDF
Research Article Autoimmunity

Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation

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.

Authors

Ângelo A. Chora, Paulo Fontoura, Andreia Cunha, Teresa F. Pais, Sílvia Cardoso, Peggy P. Ho, Lowen Y. Lee, Raymond A. Sobel, Lawrence Steinman, Miguel P. Soares

×

Figure 6

Induction of HO-1 and exposure to CO inhibit MHC class II expression in APCs.

Options: View larger image (or click on image) Download as PowerPoint
Induction of HO-1 and exposure to CO inhibit MHC class II expression in ...
(A) C57BL/6 mice were treated daily with PBS, CoPPIX, or ZnPPIX (n = 4–6) starting 2 days prior to footpad immunization. Draining lymph node cells were isolated, and surface MHC class II expression was analyzed in DCs (CD11c+) by flow cytometry 8 days after immunization. Representative histograms and quantifications (mean intensity of fluorescence; MIF) are shown as mean ± SD. (B) C57BL/6 mice were exposed to air (n = 6) or CO (450 ppm; n = 7) starting 2 days prior to immunization and continuously thereafter. Draining lymph node cells were isolated, and surface MHC class II expression was assessed in DCs (CD11c+) as in A. Representative histograms and quantification are shown as mean ± SD. (C and D) C57BL/6 mice, randomized 2 days after EAE onset, were treated daily with PBS, CoPPIX, or ZnPPIX (n = 9 per group). MHC class II expression in (C) microglia (CD45lowCD11b+) and (D) CNS-infiltrating Mφ (CD45highCD11b+) was analyzed by flow cytometry 20 days after immunization, when controls, i.e., ZnPPIX and PBS, reached maximal disease severity. Representative histograms and quantifications are shown as mean ± SD. (E and F) EAE induction and treatments were performed as in C and D. MHC class II expression was detected by immunocytochemistry and counterstained. Original magnification, ×10 (E); ×40 (F). White arrows indicate MHC class II expression. *P < 0.05; **P < 0.01.