Transgenic Inhibition of Astroglial NF-κB Improves Functional Outcome in Experimental Autoimmune Encephalomyelitis by Suppressing Chronic Central Nervous System Inflammation

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 neuro-protective 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.

Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

“…Mice were backcrossed with wild-type C57BL/6N mice for seven generations before crossing with C57BL/6N hGFAP-cre transgenic mice (NCI-MMHCC) to obtain GFAPcre:TrkBflox/flox conditional mutant mice and control TrkBflox/flox littermates. As reported, the GFAP-cre transgene mediates excision of LoxP-flanked sequences in GFAP-expressing cell lineages (Malatesta et al, 2003;Cai et al, 2007), and transgenesis in the hGFAP promoter has been extensively used to assess functions of spinal cord astrocytes in adult animals (Brambilla et al, 2005(Brambilla et al, , 2009b. Because loxP sites flank both transcription initiation sites and the first coding exon of the TrkB gene, all TrkB isoforms are deleted.…”

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

“…Experimental evidence suggests that early astrocyte activation can promote EAE. NF-kB-driven astrocyte activation contributes to a more severe course of EAE characterized by an increased expression of proinflammatory cytokines and chemokines as well as increased demyelination (2,3). This astrocytic NF-kB activation is critically regulated by IL-17-mediated activation of Act1; in the absence of astrocytic Act1 signaling, mice are largely protected from EAE and CD4 T cell infiltration to the spinal cord (4,5).…”

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

“…NF-kB is a family of transcription factors involved in a wide variety of cellular processes including cell survival, immune responses, and inflammation induced by various stimuli such as infectious agents or inflammatory cytokines (3)(4)(5). Abnormal activation of NF-kB is involved in several diseases including cancer and rheumatoid arthritis (3,(6)(7)(8). Thus, signalinduced NF-kB activation pathway has been extensively studied.…”