Flavin-Adenine Dinucleotide Induced by Antigravity Responses in the Spinal Cord Suppresses EAE Development

During transfer experimental autoimmune encephalomyelitis (tEAE), myeline specific autoreactive CD4+ T cells cross the blood brain barrier at the blood vessels of the 5th lumber (L5) cord in a manner dependent on anti-gravity responses via the soleus muscles. This crossing leads to a transient development of neural inflammation. Because the pathology does not last long, negative factors at the region may be present. To investigate the existence of these negative regulators, we performed metabolite analysis of the L5 cord with or without gravity load or electrical stimulation of the soleus muscles and identified flavin-adenine dinucleotide (FAD). The amount of FAD in the L5 cord was decreased in mice suspended by their tails, which reduced the anti-gravity response from the hindlimbs, but recovered in mice with the tail suspension plus electrical stimulation in the soleus muscles. Moreover, FAD administration suppressed the EAE pathology. Thus, FAD was induced by antigravity responses in the spinal cord and suppressed the development of neuroinflammation. Therefore, FAD could be a therapeutic candidate for diseases with neuroinflammation, particularly those involving pathogenic T cells including multiple sclerosis. Funding Statement: This work was supported by KAKENHI (M. M.), the Joint Usage/Research Center Institute for Genetic Medicine, Hokkaido University (M. M.), Takeda Science Foundation (M. M.), Institute for Fermentation Osaka (M. M.), Mitsubishi Foundation (M. M.), Naito Foundation (M. M.) and Uehara Memorial Foundation (M. M.). Declaration of Interests: The authors of this manuscript have no conflicts of interest to disclose. Ethics Approval Statement: The animal experiments used in this study were approved by the Institutional Animal Care and Use Committees of Hokkaido University.