Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation.

Abstract

In the CNS, the transcription factor NF-kappaB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-kappaB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-kappaB (glial fibrillary acidic protein-IkappaB alpha-dominant-negative mice) resulted in reduced disease severity and improved functional recovery following experimental autoimmune encephalomyelitis. At the chronic stage of the disease, transgenic mice exhibited an overall higher presence of leukocytes in spinal cord and brain, and a markedly higher percentage of CD8(+)CD122(+) T regulatory cells compared with wild type, which correlated with the timing of clinical recovery. We also observed that expression of proinflammatory genes in both spinal cord and cerebellum was delayed and reduced, whereas the loss of neuronal-specific molecules essential for synaptic transmission was limited compared with wild-type mice. Furthermore, death of retinal ganglion cells in affected retinas was almost abolished, suggesting the activation of neuroprotective mechanisms. Our data indicate that inhibiting NF-kappaB in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this disease.

• Authors: Roberta Brambilla, Trikaldarshi Persaud, Xianchen Hu, Shaffiat Karmally, Valery I Shestopalov, Galina Dvoriantchikova, Dmitry Ivanov, Lubov Nathanson, Scott R Barnum, John R Bethea
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 5 Pg. 2628-40 (Mar 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19234157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glial Fibrillary Acidic Protein
• I-kappa B Proteins
• Inflammation Mediators
• NF-kappa B
• Nfkbia protein, mouse
• NF-KappaB Inhibitor alpha

Topics

• Animals
• Astrocytes (immunology, metabolism)
• Central Nervous System (immunology, metabolism, pathology)
• Chronic Disease
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology, pathology, physiopathology)
• Female
• Gene Expression Profiling
• Glial Fibrillary Acidic Protein (deficiency, genetics)
• I-kappa B Proteins (deficiency, genetics)
• Inflammation Mediators (antagonists & inhibitors, physiology)
• Male
• Mice
• Mice, Transgenic
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, physiology)
• Oligonucleotide Array Sequence Analysis
• Severity of Illness Index