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.
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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

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Figure 5

CoPPIX induces HO-1 expression in DCs in vivo and in vitro.

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CoPPIX induces HO-1 expression in DCs in vivo and in vitro. (A) C57BL/6 ...
(A) C57BL/6 mice were randomized 2 days after EAE onset and treated daily with PBS, CoPPIX, or ZnPPIX. HO-1 and CD11c (DC) expression in spinal cords was detected by immunocytochemistry 7 days after beginning treatments and analyzed by confocal microscopy. Shown are HO-1 (left panels), CD11c (middle panels) and CD11c plus HO-1 (right panels). Original magnification, ×240. Arrows indicate positive staining. (B) Unsorted bone marrow–derived DCs (approximately 80% CD11c+) were exposed to CoPPIX or ZnPPIX, and Hmox1 mRNA and protein expression were assessed by quantitative RT-PCR and Western blotting, respectively. Hmox1 mRNA is shown as mean number of Hmox1 per HPRT mRNA molecules ± SD (n = 3 per group). (C) Bone marrow–derived DCs were purified (>98% CD11c+) and exposed to CoPPIX (50 μM for 16 hours) as in B. HO-1 (green) and CD11c (red) were detected as in A. Original magnification, ×400. (D) Expression of HO-1 was detected by Western blot in purified DCs shown in C. **P < 0.01; ***P < 0.001.