Form follows function: astrocyte morphology and immune dysfunction in SIV neuroAIDS

Abstract

Cortical function is disrupted in neuroinflammatory disorders, including HIV-associated neurocognitive disorders (HAND). Astrocyte dysfunction includes retraction of foot processes from the blood-brain barrier and decreased removal of neurotransmitters from synaptic clefts. Mechanisms of astrocyte activation, including innate immune function and the fine neuroanatomy of astrocytes, however, remain to be investigated. We quantified the number of GFAP-labeled astrocytes per mm2 and the proportion of astrocytes immunopositive for Toll-like receptor 2 (TLR2) to examine innate immune activation in astrocytes. We also performed detailed morphometric analyses of grey and white matter astrocytes in the frontal and parietal lobes of rhesus macaques infected with simian immunodeficiency virus (SIV), both with and without encephalitis, an established model of AIDS neuropathogenesis. Protoplasmic astrocytes (grey matter) and fibrous astrocytes (deep white matter) were imaged, and morphometric features analyzed using Neurolucida. Grey matter and white matter astrocytes showed no change in cell body size in animals infected with SIV regardless of encephalitic status. In SIV-infected macaques, both grey and white matter astrocytes had shorter, less ramified processes, resulting in decreased cell arbor compared with controls. SIV-infected macaques with encephalitis showed decreases in arbor length in white matter astrocytes and reduced complexity in grey matter astrocytes compared to controls. These results provide the first evidence that innate immune activation of astrocytes is linked to altered cortical astrocyte morphology in SIV/HIV infection. Here, we demonstrate astrocyte remodeling is correlated with infection. Perturbed neuron-glia signaling may be a driving factor in the development of HAND.

New advances on glial activation in health and disease

“…In the same way that neuronal dendrites are adaptable and respond to changes in CNS activity by altering their structure, astrocytic processes dynamically alter their morphology and interact with synapses in response to their environment [75] . Morphological changes in astrocytes have been documented in chronic stress [76] , traumatic brain injury [77] , neurodegenerative disease [78] , CNS viral and bacterial infections [79,80] , and behavioral and mood disorders [81,82] . Experimentally, changes in astrocyte morphology have been reported after ethanol administration [83] , dietary-induced obesity [84] , and physical exercise [85] .…”

“…Atrophic astrocytes result in reduced support for neuronal networks, which may ultimately decrease neuronal connectivity and plasticity. We have recently shown that, in the setting of simian immunodeficiency virus (SIV) infection and SIV-induced encephalitis, gray and white matter astrocytes retract their processes resulting in an overall decreased arbor irrespective of encephalitic status [79] . It is hypothesized that reduced numbers of astrocytes is directly linked to disruptions in cognitive behavior and that astrocyte loss may be a primary driver of pathology [100,101] .…”

“…Heterogeneity of glial activation by increasing the likelihood of the cells to respond to subsequent inflammatory insults [152] . HIV infection increases TLR2 expression in astrocytes, which can increase susceptibility to additional insults, either from a secondary/opportunistic infection or from a second round of virus entering the brain [79,153] . Additionally, enhanced TLR expression would upregulate the secretion of proinflammatory cytokines by astrocytes [154,155] , triggering a self-sustaining inflammatory loop and longterm glial activation.…”

Neuropathogenesis of HIV: From Initial Neuroinvasion to HIV-Associated Neurocognitive Disorder (HAND)

“…At the same time, research in an SIV model showed that infected astrocytes shows changes in morphology, namely decreased arborization and dendritic length in both white and grey astrocytes. This suggests that infected astrocytes may create interruptions in glialneuronal signaling, leading to brain atrophy and the symptoms associated with HAND (72). A synthesis of these findings may indicate that astrocytes are not simply passively infected, but in fact attempt to rid the brain of HIV only to fall prey to HIV.…”

Development of a simple in vitro mature mixed glial model to investigate differential expression of cell markers on glial cells and their potential as targets in multiple sclerosis

“…It could be speculated that binding of the anti-GLAST 152-172 antibody on the extracellular surface of the astrocytes induces a signal that results in the rearrangement of GFAP within the cell. In addition, it has recently been reported that immune activation of astrocytes is linked to altered cortical astrocyte morphology, as identified by GFAP staining, in an infection model (Lee et al, 2014). Therefore, even though some of the astrocytes in the cultures treated with anti-GLAST 152-172 antibody plus complement were not killed, the resulting observations suggest that the antibody did indeed have some potentially pathogenic effects on the astrocytes.…”