The choreography of neuroinflammation in Huntington's disease

Abstract

Currently, the concept of 'neuroinflammation' includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. The roles of brain-resident and peripheral immune cells in these inflammatory settings are poorly understood, and it is unclear whether neuroinflammation results from immune reaction to neuronal dysfunction/degeneration, and/or represents cell-autonomous phenotypes of dysfunctional immune cells. Here, we review recent studies examining these questions in the context of Huntington's disease (HD), where mutant Huntingtin (HTT) is expressed in both neurons and glia. Insights into the cellular and molecular mechanisms underlying neuroinflammation in HD may provide a better understanding of inflammation in more complex neurodegenerative disorders, and of the contribution of the neuroinflammatory component to neurodegenerative disease pathogenesis.

Keywords: Huntington's disease; astrocytes; macrophages; microglia; neuroinflammation.

Figure 1

A model for mutant Huntingtin (HTT) microglia cell-autonomous activation and reactive microglia responses to neurodegeneration. In the presence of mutant HTT, increasing PU.1 expression and PU.1- CCAAT/enhancer-binding protein (C/EBP) promoter binding leads to increased enhancer activity under basal conditions that results in increased expression of basal pro-inflammatory and neurotoxic genes. This phenomenon increases the sensitivity to pro-inflammatory signals. In fact, under conditions of sterile inflammation, mutant HTT-expressing microglia appear to be more efficient in inducing neuronal death. We hypothesize that components of dead neurons or mutant HTT aggregates could trigger sterile inflammation, and this, in turn, could lead to further microglia activation, resulting in increased neuronal death and the activation of a chronic ‘feed-forward loop’. Adapted from [34]. Abbreviations: IL, interleukin; TNF, tumor necrosis factor.

Figure 2

The choreography of neuroinflammation in Huntington’s disease. Expression of mutant Huntingtin (mHTT) in neurons triggers cell-autonomous neuronal degeneration and apoptosis (top center). In parallel, expression of mHTT in microglia triggers cells autonomous pro-inflammatory activation characterized by the release of pro-inflammatory cytokines, reactive oxygen species (ROS), and neurotoxic metabolites (center left). At the same time, expression of mHTT in astrocytes induces the cell-autonomous repression of several factors involved in the support of neurons wellbeing, such as, for example, Chemokine (C-C motif) ligand (CCL)-5, transforming growth factor (TGF)-β, and so on (center right). With the progression of neurodegeneration, endogenous molecules, such as components of dead neurons, protein aggregates, and potentially extracellular mHTT could be detected as DAMPs, inducing an innate immune response similar to what happens when amyloid (A)-β is phagocytosed by macrophages (center). Thus, enhanced pro-inflammatory microglia activation supported by pro-inflammatory cytokine-triggered astrocyte activation will result in further damage to neurons and the activation of a chronic ‘feed-forward loop’ of neurodegeneration. Abbreviations: IL, interleukin; NF, nuclear factor; TNF, tumor necrosis factor.