Is NF‐κB from astrocytes a decision maker of neuronal life or death? (Commentary on Dvoriantchikova et al.)

Abstract

From Claude Bernard’s ‘milieu interieur’ to Walter Cannon’s homeostasis concept, the harmony of the neuron or glial intracellular environment has been a defining principle of cell integrity. Astrocytes are a harmony-building component of the nervous system, wrapping up synapses, shaping the neurovascular unit, preventing excitotoxic concentrations of extracellular glutamate with transporters of this amino acid neurotransmitter, and by secreting neurotrophins and anti-inflammatory cytokines, such as interleukin (IL)-10. An unbalanced environment is created within neural cells by a variety of bioactive molecules, which include chemokines, pro-inflammatory mediators, and cytokines, made and secreted by activated astrocytes upon injury, brain ischemia-reperfusion, or neurodegeneration. In turn, this abnormal environment becomes a major initiator and propagator of neuroinflammation. In this issue of EJN, Dvoriantchikova et al. (2009) show that astroglial NF-κB is a critical regulator of retinal ganglion cell survival against ischemia-reperfusion injury. The design of this study is based upon inhibition of NF-κB in astrocytes by overexpressing an N-terminal-truncated form of inhibitor of nuclear factor kappa B alpha (IκBα) using a GFAP promoter. Thus, the GFAP-IκBα-dn transgenic mice display inhibited NF-κB function in astrocytes. The expression of the transgene is restricted to astrocytes and GFAP-expressing non-myelinating Schwann cells, without ectopic expression in neurons or in other tissues (Brambilla et al., 2005). Dvoriantchikova et al. (2009) induced unilateral transient retinal ischemia (duration 60 min) by raising the intraocular pressure above normal systolic levels, followed by reperfusion, which led to retinal ganglion cell death. Their study shows that transgenic inhibition of astroglial NF-κB leads to decreased ischemic-reperfusion-induced retinal ganglion cell death. Astrocytes display a dual behavior when the CNS is confronted with injury and disease. In particular, astrocytes have beneficial functions during the early stages of injury, whereas sustained activation of astrocytes enhances neuroinflammation, as well as cell injury and dysfunction. Astrocyte activation, or astrogliosis, is a rapid response to changes in the CNS environment during ischemia-reperfusion and in models of epileptogenesis (Cole-Edwards et al., 2006). NF-κB, an inducible transcription factor, acts as a master regulator of immune functions, inflammatory responses and secondary injury processes. Neuronal NF-κB is a mediator of ischemia-triggered neuronal death, whereas astrocytic NF-κB is thought to be neuroprotective. The inner molecular workings of NF-κB signaling and regulation are still being explored (Hayden & Ghosh, 2008). Cytokines such as TNFα, which are produced and released by astrocytes, can recruit microglia and macrophages, thereby establishing autocrine and paracrine feedback circuitry. Thus, astroglial-originating mediators greatly enhance microglia/macrophage responses. Overall, these events are driven by astroglial NF-κB, which establishes an inflammatory intracellular environment. Inactivation of astroglial NF-κB (Dvoriantchikova et al., 2009) abrogates the establishment of this perturbed cellular environment. The authors conclude that suppression of retinal astroglial NF-κB induces survival of retinal ganglion cells upon ischemia-reperfusion injury by inhibition of the expression of inflammatory mediators, reactive oxygen, and nitrosylative species, as well as other neurotoxicity pathways. Some of our recent work demonstrates that the new omega-3 essential fatty acid-derived mediator neuroprotectin D1 (NPD1) inhibits brain ischemia-reperfusion-induced NF-κB expression, as well as pro-inflammatory genes and leukocyte infiltration, and in turn exerts neuroprotection (Marcheselli et al., 2003). It will be of interest to define whether the target of NPD1 is the astrocytic NF-κB. Since retinal ganglion cells die in glaucoma, these observations (Dvoriantchikova et al., 2009) are also of interest in the pathophysiology of this disease. Astrocytes and inflammatory cells are active participants in optic nerve head damage in glaucoma. Therefore, this study opens an avenue to explore the significance of astroglial NF-κB in glaucoma. In addition, it also will be important to determine whether the transgene is expressed by Müeller cells, which are GFAP positive at their end feet (Fernandez-Bueno et al., 2008), located at the same retinal layer as the retinal ganglion cells. Along with the current study (Dvoriantchikova et al., 2009), the recent report that transgenic inhibition of astroglial NF-κB induces neuroprotection in experimental autoimmune encephalomyelitis (Brambilla et al., 2009) imply a broader implication of astroglial signaling for multiple sclerosis, stroke, and other neurodegenerative diseases. The interactions observed between survival and neuroinflammatory signaling, driven by the master regulator NF-κB of astrocytes, will generate a greater understanding of the signaling involved in neuronal life or death decisions.