CLINICAL OR BASIC ORIGINAL STUDY Type 3 Deiodinase Expression in Inflammatory Spinal Cord Lesions in Rat Experimental Autoimmune Encephalomyelitis Anita Boelen, 1, * Joanna Mikita, 2, * Claudine Boiziau, 2 Olivier Chassande, 3 Eric Fliers, 1 and Klaus G. Petry 2 Background: We have shown substantial expression of type 3 deiodinase (D3, a major enzyme involved in the inactivation of thyroid hormone) in infiltrating leukocytes in several models of inflammation. Recently, thyroid hormone has been shown to improve remyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. As induction of D3 may play an important role in decreasing local bio- availability of thyroid hormone at inflammation sites, we hypothesized that D3 is induced in spinal cord inflammatory lesions in EAE. Methods: The aim of the study was to evaluate D3 expression in spinal cord inflammatory lesions of EAE Dark Agouti rats and to investigate D3 induction in activated monocytes. Results: Here, we show marked expression of D3 by granulocytes and macrophages in spinal cord inflammatory lesions of EAE rats. We further confirm induction of D3 expression in vitro in monocytes that were activated toward proinflammatory or immunomodulatory phenotypes. Conclusions: We observed increased D3 expression both in spinal cord inflammatory lesions during EAE and in activated monocytes. Although increased D3 expression theoretically results in decreased triiodothyronine availability, it is unknown at present whether reduced local triiodothyronine concentrations are involved in impaired remyelination as observed during EAE. Introduction M ultiple sclerosis ( MS) is characterized by acute focal inflammatory demyelinating lesions followed by axo- nal loss in central nervous system (CNS) (1,2). Although spontaneous remyelination may occur, remyelination failure has been reported in inflammatory MS lesions with axonal loss (3). This failure was observed despite the presence of oligodendrocyte precursor cells (OPCs), which generate ma- ture oligodendrocytes forming myelin sheaths. Until now, several factors have been identified to be involved in OPC differentiation, that is, chemokines (4), growth factors (5,6), activated cAMP responsive element binding (CREB) proteins (7), and thyroid hormone (8). Recent studies showed that thyroid hormone protects ax- ons against damage induced by inflammatory processes during MS. Thyroid hormone activated OPCs in experimental allergic encephalomyelitis (EAE), an animal model of MS, by increasing myelin-basic protein content in the spinal cord of affected animals (9). Further, the pulsatile administration of thyroxine (T 4 ) during the acute EAE improved remyelination by increasing OPC cell numbers and oligodendrocyte mark- ers, resulting in faster morphological reorganization of myelin sheaths in the white matter during chronic EAE (10). Thyroid hormone has also been shown to improve remyelination in cuprizone-induced demyelination in mice (11). Recently, a study of Fernandez et al. showed that triiodothyronine (T 3 ) completely restores the impaired oligodendrocyte genera- tion observed in neurospheres derived form EAE rats, sug- gesting that T 3 may favor remyelination in demyelinating disorders (12). Extrathyroidal or peripheral thyroid hormone metabolism is predominantly mediated by deiodinating enzymes, which are organ specific and have different metabolic functions (13). D1 and D2 catalyze conversion of pro-hormone T 4 into bio- active hormone T 3 , whereas type 3 deiodinase (D3) catalyzes inactivation of T 4 and T 3 into reverse (r)T 3 and 3,3-diiodo- thyronine (T 2 ), respectively. We have recently shown that D3 1 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2 Neurobiology of Myelin Disorders Laboratory and 3 INSERM U 577, Universite ´ Victor Segalen Bordeaux 2, Bordeaux, France. *These two authors contributed equally to this work. THYROID Volume 19, Number 12, 2009 ª Mary Ann Liebert, Inc. DOI: 10.1089=thy.2009.0228 1