Innate Immune-Mediated Neuronal Injury Consequent to Loss of Astrocytes

Abstract

Neuronal injury and loss are recognized features of neuroinflammatory disorders, including acute and chronic encephalitides and multiple sclerosis; destruction of astrocytes has been demonstrated in cases of Rasmussen encephalitis. Here, we show that innate immune cells (i.e. natural killer [NK] and gammadelta T cells) cause loss of neurons from primary human neuron-enriched cultures by destroying the supporting astrocytes. Interleukin 2-activated NK cells caused loss of astrocytes within 1 hour, whereas neurons were lost at 4 hours. Time-lapse imaging indicated that delayed neuron loss was due to early destruction of supporting astrocytes. Selective blocking of astrocyte death with anti-NKG2D antibodies reduced neuron loss, as did blocking of CD54 on astrocytes. gammadelta T cells also induced astrocyte cytotoxicity, leading to subsequent neuronal displacement. In astrocytes, NK cells caused caspase-dependent fragmentation of the intermediate filament proteins glial fibrillary acidic protein and vimentin, whereas anti-CD3-activated T cells produced fragmentation to a lesser extent and without measurable cytotoxicity. Glial fibrillary acidic protein fragmentation was also demonstrated in lysates from chronic multiple sclerosis plaques but not from normal control white matter. These data suggest that non-major histocompatibility complex-restricted immune effector cells may contribute to neuron loss in neuroinflammatory disorders indirectly through injury of glia.

A selective role of NKG2D in inflammatory and autoimmune diseases

“…This conclusion fits with genetic and in vitro studies that have provided suggestive evidence for a role of NKG2D in multiple sclerosis in humans [15, 39, 40]. NKG2D-deficient mice showed reduced disease only under limiting conditions, suggesting the possibility that other activating immune receptors or stimuli can substitute for NKG2D in initiating disease in this model, or that NKG2D plays a secondary role that can amplify inflammation.…”

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

“…In addition to playing a role in the inflammatory reaction, astrocytes can themselves be the primary target of the autoimmune process, exemplified by the disorder NMO. Astrocyte damage is also observed in active MS cases (Darlington et al, ; Stopnicki et al, ).…”

Role of the innate immune system in the pathogenesis of multiple sclerosis

“…In vitro NK cells show cytotoxic activity towards oligodendrocytes and other glial cells, such as astrocytes and microglial cells (figure 2) during inflammation. This cytotoxic interaction is mediated between the activating NKG2D receptor, expressed by NK cells, and its ligands, such as MHC Class I chain-related molecules A and B (MICA/B) and UL16-binding proteins 1, 2 and 3 (ULBPs) expressed by oligodendrocytes and fetal astrocytes (Saikali et al, 2007), and also between other molecules, such as lymphocyte function-associated antigen 1 receptors (LFA-1) and CD54 on astrocytes (Darlington et al, 2008). These interactions result in a caspase-dependent cleavage of astrocyte intermediate filaments (Darlington et al, 2008).…”

“…This cytotoxic interaction is mediated between the activating NKG2D receptor, expressed by NK cells, and its ligands, such as MHC Class I chain-related molecules A and B (MICA/B) and UL16-binding proteins 1, 2 and 3 (ULBPs) expressed by oligodendrocytes and fetal astrocytes (Saikali et al, 2007), and also between other molecules, such as lymphocyte function-associated antigen 1 receptors (LFA-1) and CD54 on astrocytes (Darlington et al, 2008). These interactions result in a caspase-dependent cleavage of astrocyte intermediate filaments (Darlington et al, 2008). NK cells can kill microglial cells by release of perforin by interactions involving NKG2D and NKp46 receptors on NK cells (Lunemann et al, 2008).…”