Inhibition of astroglial NF-kappaB enhances oligodendrogenesis following spinal cord injury

Abstract

BackgroundAstrocytes are taking the center stage in neurotrauma and neurological diseases as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting NF-κB activation in astrocytes, using a transgenic mouse model (GFAP-IκBα-dn mice), results in improved functional recovery, increased white matter preservation and axonal sparing following spinal cord injury (SCI). In the present study, we sought to determine whether this improvement, due to inhibiting NF-κB activation in astrocytes, could be the result of enhanced oligodendrogenesis in our transgenic mice.MethodsTo assess oligodendrogenesis in GFAP-IκBα-dn compared to wild-type (WT) littermate mice following SCI, we used bromodeoxyuridine labeling along with cell-specific immuno-histochemistry, confocal microscopy and quantitative cell counts. To further gain insight into the underlying molecular mechanisms leading to increased white matter, we performed a microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-IκBα-dn and WT littermate mice.ResultsInhibition of astroglial NF-κB in GFAP-IκBα-dn mice resulted in enhanced oligodendrogenesis 6 weeks following SCI and was associated with increased levels of myelin proteolipid protein compared to spinal cord injured WT mice. The microarray data showed a large number of differentially expressed genes involved in inflammatory and immune response between WT and transgenic mice. We did not find any difference in the number of microglia/leukocytes infiltrating the spinal cord but did find differences in their level of expression of toll-like receptor 4. We also found increased expression of the chemokine receptor CXCR4 on oligodendrocyte progenitor cells and mature oligodendrocytes in the transgenic mice. Finally TNF receptor 2 levels were significantly higher in the transgenic mice compared to WT following injury.ConclusionsThese studies suggest that one of the beneficial roles of blocking NF-κB in astrocytes is to promote oligodendrogenesis through alteration of the inflammatory environment.

Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling

“…Interestingly, TNF has been shown to have a role in the pathophysiology of autoimmune demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) (Finsen et al, 2002) and the role of TNFR1-mediated TNF signaling in causing demyelination has been widely investigated by different authors (Arnett et al, 2001; Eugster et al, 1999; Probert et al, 2000). Finally, we and others have demonstrated that signaling mediated by transmembrane TNF, occurring mainly through TNFR2, has been proven to be essential for axon and myelin preservation and to promote remyelination (Bracchi-Richard et al, 2013; Brambilla et al, 2011; Taoufik et al, 2011). Based upon this evidence we sought to determine whether neuropathic pain-associated depression is related to hippocampal neuroplasticity and myelin alterations, and whether TNF signaling through TNFR1 plays a role in these events.…”

“…A possible mechanism underlying the increased expression of TNFR2 in TNFR1 −/− mice following injury could be represented by NF-κB activation through TNFR1. In a recent study we determined that in transgenic mice in which NF-κB activation is selectively inhibited in astrocytes, TNFR2 expression was significantly upregulated in the chronically injured spinal cords compared to the levels measured in the spinal cords of injured wild-type mice (Bracchi-Ricard et al, 2013). These data suggest that NF-κB activation acts as a negative regulator of TNFR2 expression.…”

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…Additionally, the marker of A1 astrocytes, complement component 3 (C3), is upregulated in an NFκB-dependent manner [7]. Moreover, blocking NFκB activity in astrocytes promotes oligodendrogenesis and axonal sparing through alteration of the inflammatory environment following SCI [8].…”

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

“…However, astrocytes appear to create a permissive environment that promotes OPC recruitment, migration and differentiation [172]. Accordingly, astrocytes promote oligodendrogenesis through the secretion of tissue inhibitor of metalloproteinase-1 [173, 174], and inhibition of astroglial NF-κB signaling enhances oligodendrogenesis following spinal cord injury [175]. Moreover, despite successful recruitment of OPC within a demyelinating injury in the adult rat spinal cord, these precursors fail to remyelinate the axons in the absence of astrocytes [176].…”