Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis.
IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-gamma and TNF-alpha mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte "sink" that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.
Quintana
Albert
A
School of Molecular and Microbial Biosciences, University of Sydney, New South Wales, Australia.
Müller
Marcus
M
Frausto
Ricardo F
RF
Ramos
Raquel
R
Getts
Daniel R
DR
Sanz
Elisenda
E
Hofer
Markus J
MJ
Krauthausen
Marius
M
King
Nicholas J C
NJ
Hidalgo
Juan
J
Campbell
Iain L
IL
D000818:Animals; D015551:Autoimmunity; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000473:pathology; D002633:Chemotaxis; D016207:Cytokines / Q000032:analysis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000009:adverse effects; D063308:Myelin-Oligodendrocyte Glycoprotein; D010243:Paralysis
D016207:Cytokines; D015850:Interleukin-6; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein