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

Roberta Brambilla, Trikaldarshi Persaud, Xianchen Hu, Shaffiat Karmally, Valery I Shestopalov, Galina Dvoriantchikova, Dmitry V Ivanov, Lubov Nathanson, Scott R. Barnum, John R. Bethea

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Abstract

In the CNS, the transcription factor NF-κB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-κB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-κB (glial fibrillary acidic protein-IκBα-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-κB in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this disease.

Original languageEnglish
Pages (from-to)2628-2640
Number of pages13
JournalJournal of Immunology
Volume182
Issue number5
DOIs
StatePublished - Mar 1 2009

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Autoimmune Experimental Encephalomyelitis
Central Nervous System
Inflammation
Astrocytes
Spinal Cord
Retinal Ganglion Cells
Glial Fibrillary Acidic Protein
Wounds and Injuries
Neuroprotective Agents
Regulatory T-Lymphocytes
Synaptic Transmission
Cerebellum
Transgenic Mice
Retina
Leukocytes
Chronic Disease
Transcription Factors
Gene Expression
Brain
Genes

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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Transgenic inhibition of astroglial NF-κB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. / Brambilla, Roberta; Persaud, Trikaldarshi; Hu, Xianchen; Karmally, Shaffiat; Shestopalov, Valery I; Dvoriantchikova, Galina; Ivanov, Dmitry V; Nathanson, Lubov; Barnum, Scott R.; Bethea, John R.

In: Journal of Immunology, Vol. 182, No. 5, 01.03.2009, p. 2628-2640.

Research output: Contribution to journalArticle

Brambilla, Roberta ; Persaud, Trikaldarshi ; Hu, Xianchen ; Karmally, Shaffiat ; Shestopalov, Valery I ; Dvoriantchikova, Galina ; Ivanov, Dmitry V ; Nathanson, Lubov ; Barnum, Scott R. ; Bethea, John R. / Transgenic inhibition of astroglial NF-κB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. In: Journal of Immunology. 2009 ; Vol. 182, No. 5. pp. 2628-2640.
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