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Investigating the role of bilirubin system in experimental autoimmune encephalomyelitis and characterizing it as a novel strategy for treatment Liu, Yingru


Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune inflammatory disease of the CNS that serves as a model for the human demyelinating disease, multiple sclerosis. Multiple factors, including free radicals, complement and antibodies, play an important pathogenic role in this disease. Bilirubin, an endogenous product of heme degradation in mammals, was once considered a toxic waste product, but is in recent decades recognized as a potent antioxidant of physiological importance. It has also been demonstrated that bilirubin may possess immunomodulatory and anti-inflammatory properties due to its high lipophilia and its direct interaction with inflammatory cell membranes. We hypothesized that bilirubin could play a protective role in EAE and might represent a novel effective target for the treatment of this disease. First, we demonstrated that during EAE, both heme oxygenase-1 and biliverdin reductase (BVR), which catalyze heme catabolism and generate bilirubin, were strongly induced in the inflamed lesions, and the concentration of bilirubin was subsequently increased. Bilirubin as a potent antioxidant suppressed EAE effectively. Histological examination showed that if administered before the onset of clinical EAE, bilirubin protected the integrity of the blood-brain barrier (BBB) from free radical-induced permeability changes such that cell invasion and the resulting pathology were minimized. If administered after the onset of disease, bilirubin penetrated the already compromised BBB, scavenged the free radicals that are directly responsible for CNS tissue damage, and promoted recovery of the animals. In contrast, depletion of endogenously produced bilirubin dramatically worsened EAE. Our results further revealed that bilirubin was not only an antioxidant, but also a powerful immunomodulatory agent. Bilirubin exerted its potent immunosuppressive activity both in vitro and in vivo in the treatment of EAE. The strong immunosuppressive effects of bilirubin could not be attributed to its antioxidant property. Bilirubin significantly inhibited both antigen-specific and polyclonal T cell responses. Bilirubin suppressed T cell proliferation through multifaceted actions, including its inhibitory effects on TCR signaling, costimulator activities, and immune transcription factors activation. In vivo, the protective effect of bilirubin treatment in EAE was associated with changes in the antigen-specific autoimmune response. Bilirubin treatment impaired the ability of antigen-specific T cells to induce EAE by adoptive transfer, while other similar strong antioxidants completely lacked this effect. Recent studies show that BVR can physiologically regenerate bilirubin in a catalytic cycle. Compared with bilirubin, BVR is soluble and nontoxic. We surmised that BVR might prove to be a novel, safer strategy for treatment. Our results demonstrated that BVR ameliorated both clinical and pathological signs of EAE more efficiently than traditional antioxidant enzymes. Interestingly, BVR achieved its strong therapeutic effects without significantly increasing the biological concentration of bilirubin, which is cytotoxic at high levels. In summary, we demonstrate that bilirubin possesses multiple physiological functions and plays an important protective role in EAE. These data indicate its potential in the treatment of multiple sclerosis and other stress or immune-mediated diseases.

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