Inactivation of astroglial NF‐κB promotes survival of retinal neurons following ischemic injury

Abstract

Reactive astrocytes have been implicated in neuronal loss following ischemic stroke. However, the molecular mechanisms associated with this process are yet to be fully elucidated. In this work, we tested the hypothesis that astroglial NF-κB, a key regulator of inflammatory responses, is a contributor to neuronal death following ischemic injury. We compared neuronal survival in the ganglion cell layer after retinal ischemia-reperfusion in wild type and in GFAP-IκBα-dn transgenic mice, where the NF-κB classical pathway is suppressed specifically in astrocytes. The GFAP-IκBα-dn mice showed significantly increased survival of neurons in the ganglion cell layer following ischemic injury as compared to WT littermates. Neuroprotection was associated with significantly reduced expression of pro-inflammatory genes, encoding Ccl2 (Mcp1), Cxcl10 (IP10), Icam1, Vcam1, several subunits of NADPH oxidase and NO synthase in the retinas of GFAP-IκBα-dn mice. These data suggest that certain NF-κB-regulated pro-inflammatory and redox-active pathways are central to glial neurotoxicity induced by ischemic injury. The inhibition of these pathways in astrocytes may represent a feasible neuroprotective strategy for retinal ischemia and stroke.

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

“…8 C), both iNOS and Astrocytes are important regulators of neuroinflammation and neurodegeneration. Published data show that NF-B signaling in astrocytes promotes neurotoxicity and CNS inflammation (Brambilla et al, 2009a,b;Dvoriantchikova et al, 2009;Fu et al, 2010). In this study, we describe for the first time that, as in a typical inflammatory pathway, the astrocytic response toward neurotrophins supports EAE expression by fostering a permissive environment for immune cell infiltration and neurodegeneration.…”

Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation

“…It is well established that astrocytes can amplify neuroinflammation in pathological situations by the permeabilization of the bloodbrain barrier and the production of chemokines and cytokines (Glass et al, 2010;Wilson et al, 2010). Inactivation of NF-B signaling reduces this proinflammatory function of astrocytes (Brambilla et al, 2005Dvoriantchikova et al, 2009).…”

Astrocytes in Neurodegenerative Disease: Table 1.

“…Inhibition of astroglial NF-kB resulted in limiting tissue injury and impaired functional recovery after contusive SCI (Brambilla et al 2005). This also increased neuronal sparing and sprouting of spinal tract axons (Brambilla et al 2009a), increased neuronal survival in the retinal glial cell (RGC) layer after ischemia-reperfusion injury (Dvoriantchikova et al 2009), and reduced disease incidence and severity and promoted significant functional recovery in murine experimental autoimmune encephalomyelitis (EAE) (Brambilla et al 2009b). Activation of NF-kB in astrocytes is also thought to contribute to pathogenesis in HD (Hsiao et al 2013).…”