Neuronal I kappa B kinase beta protects mice from autoimmune encephalomyelitis by mediating neuroprotective and immunosuppressive effects in the central nervous system.

Abstract

Some aspects of CNS-directed autoimmunity in multiple sclerosis are modeled in mice by immunization with myelin Ags where tissue damage is driven by myelin-reactive Th1 and Th17 effector lymphocytes. Whether the CNS plays an active role in controlling such autoimmune diseases is unknown. We used mice in which IkappaB kinase beta was deleted from Ca(2+)/calmodulin-dependent kinase IIalpha-expressing neurons (nIKKbetaKO) to investigate the contribution of neuronal NF-kappaB to the development of myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis. We show that nIKKbetaKO mice developed a severe, nonresolving disease with increased axon loss compared with controls and this was associated with significantly reduced CNS production of neuroprotective factors (vascular endothelial growth factor, CSF1-R, and FLIP) and increased production of proinflammatory cytokines (IL-6, TNF, IL-12, IL-17, and CD30L) and chemokines. The isolation of CNS-infiltrating monocytes revealed greater numbers of CD4(+) T cells, reduced numbers of NK1.1(+) cells, and a selective accumulation of Th1 cells in nIKKbetaKO CNS from early in the disease. Our results show that neurons play an important role in determining the quality and outcome of CNS immune responses, specifically that neuronal IkappaB kinase beta is required for neuroprotection, suppression of inflammation, limitation of Th1 lymphocyte accumulation, and enhancement of NK cell recruitment in experimental autoimmune encephalomyelitis-affected CNS and stress the importance of neuroprotective strategies for the treatment of multiple sclerosis.

• Authors: Mary Emmanouil, Era Taoufik, Vivian Tseveleki, Sotiris-Spyros Vamvakas, Theodore Tselios, Michael Karin, Hans Lassmann, Lesley Probert
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 12 Pg. 7877-89 (Dec 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 20007573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Inflammation Mediators
• I-kappa B Kinase

Topics

• Animals
• Axons (immunology, pathology)
• Cell Death (genetics, immunology)
• Cell Migration Inhibition (genetics, immunology)
• Central Nervous System (enzymology, immunology, pathology)
• Chronic Disease
• Encephalomyelitis, Autoimmune, Experimental (enzymology, genetics, immunology, prevention & control)
• I-kappa B Kinase (deficiency, genetics, physiology)
• Immunosuppressive Agents (metabolism, pharmacology)
• Inflammation Mediators (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (enzymology, immunology, pathology)
• Th1 Cells (immunology, pathology)