Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation.
Iron accumulation occurs in the CNS in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying such iron accumulation are not fully understood. We studied the expression and cellular localization of molecules involved in cellular iron influx, storage, and efflux. This was assessed in two mouse models of EAE: relapsing-remitting (RR-EAE) and chronic (CH-EAE). The expression of molecules involved in iron homeostasis was assessed at the onset, peak, remission/progressive and late stages of the disease. We provide several lines of evidence for iron accumulation in the EAE spinal cord which increases with disease progression and duration, is worse in CH-EAE, and is localized in macrophages and microglia. We also provide evidence that there is a disruption of the iron efflux mechanism in macrophages/microglia that underlie the iron accumulation seen in these cells. Macrophages/microglia also lack expression of the ferroxidases (ceruloplasmin and hephaestin) which have antioxidant effects. In contrast, astrocytes which do not accumulate iron, show robust expression of several iron influx and efflux proteins and the ferroxidase ceruloplasmin which detoxifies ferrous iron. Astrocytes therefore are capable of efficiently recycling iron from sites of EAE lesions likely into the circulation. We also provide evidence of marked dysregulation of mitochondrial function and energy metabolism genes, as well as of NADPH oxidase genes in the EAE spinal cord. This data provides the basis for the selective iron accumulation in macrophage/microglia and further evidence of severe mitochondrial dysfunction in EAE. It may provide insights into processes underling iron accumulation in MS and other neurodegenerative diseases in which iron accumulation occurs.
Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada.
Juan G
JG
Zarruk
Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada.
Jennifer L
JL
Berard
Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada.
Rosmarini
R
Passos dos Santos
Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada.
Antje
A
Kroner
Dept of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, N210 Beadle Center, Lincoln, NE 68588-0664 USA.
Jaekwon
J
Lee
Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Paolo
P
Arosio
Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal H3G 1A4, Quebec, Canada. Electronic address: sam.david@mcgill.ca.
Samuel
S
David
D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D005260:Female; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D005620:Freund's Adjuvant / Q000633:toxicity; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019189:Iron Metabolism Disorders / Q000209:etiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D039481:CD11b Antigen; D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D005293:Ferritins; D005620:Freund's Adjuvant; D005904:Glial Fibrillary Acidic Protein; D064451:Hepcidins; D007501:Iron; D008565:Membrane Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011990:Receptors, Transferrin; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C117324:Heph protein, mouse; C547161:TPPP protein, mouse; C480029:Tfrc protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55)
Ceruloplasmin; Experimental autoimmune encephalomyelitis; Ferroportin; Hepcidin; Iron; Iron efflux; Iron influx; MS; Macrophage; Microglia