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Deficiency of Fatty Acid-Binding Proteins in Mice Confers Protection from Development of Experimental Autoimmune Encephalomyelitis¹

Joseph M. Reynolds^*, Qiaohong Liu^*, Katherine C. Brittingham^*, Yawei Liu^*, Michael Gruenthal, Cem Z. Gorgun, Gökhan S. Hotamisligil, Robert D. Stout^* and Jill Suttles^2,*

^* Department of Microbiology and Immunology and Department of Neurology, School of Medicine, University of Louisville, Louisville, KY 40292; and Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115

Fatty acid-binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. Recent studies have demonstrated the ability of FABPs to simultaneously regulate metabolic and inflammatory pathways. We investigated the role of adipocyte FABP and epithelial FABP in the development of experimental autoimmune encephalomyelitis to test the hypothesis that these FABPs impact adaptive immune responses and contribute to the pathogenesis of autoimmune disease. FABP-deficient mice exhibited a lower incidence of disease, reduced clinical symptoms of experimental autoimmune encephalomyelitis and dramatically lower levels of proinflammatory cytokine mRNA expression in CNS tissue as compared with wild-type mice. In vitro Ag recall responses of myelin oligodendrocyte glycoprotein 35–55-immunized FABP^–/– mice showed reduced proliferation and impaired IFN- production. Dendritic cells deficient for FABPs were found to be poor producers of proinflammatory cytokines and Ag presentation by FABP^–/– dendritic cells did not promote proinflammatory T cell responses. This study reveals that metabolic-inflammatory pathway cross-regulation by FABPs contributes to adaptive immune responses and subsequent autoimmune inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Multiple Sclerosis Society Grant RG 3374 (to J.S.), National Institutes of Health Grants AI48850 (to J.S.) and DK064360 (to G.S.H.), and in part by American Heart Association Predoctoral Fellowships (to J.M.R. and K.C.B.) and the Commonwealth of Kentucky Research Challenge Trust Fund (to J.S. and R.D.S.).

² Address correspondence and reprint requests to Dr. Jill Suttles, Department of Microbiology and Immunology, School of Medicine, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40292. E-mail address: jill.suttles{at}louisville.edu

³ Abbreviations used in this paper: A-FABP, adipocyte fatty acid-binding protein; E-FABP, epidermal FABP; PPAR, peroxisome proliferator-activating receptor; IKK, IB kinase; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein.

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