Astrocyte pathology in Alexander disease causes a marked inflammatory environment

Abstract

Astrocytes and microglia are commonly involved in a wide variety of CNS pathologies. However, they are typically involved in a secondary response in which many cell types are affected simultaneously and therefore it is difficult to know their contributions to the pathology. Here, we show that pathological astrocytes in a mouse model of Alexander disease (AxD; GFAP (Tg);Gfap (+/R236H)) cause a pronounced immune response. We have studied the inflammatory response in the hippocampus and spinal cord of these mice and have found marked microglial activation, which follows that of astrocytes in a spatial pathological progression, as shown by increased levels of Iba1 and microglial cell (Iba1+) density. RNA sequencing and subsequent gene ontology (GO) analysis revealed that a majority of the most upregulated genes in GFAP (Tg);Gfap (+/R236H) mice are directly associated with immune function and that cytokine and chemokine GO attributes represent nearly a third of the total immune attributes. Cytokine and chemokine analysis showed CXCL10 and CCL2 to be the most and earliest increased molecules, showing concentrations as high as EAE or stroke models. CXCL10 was localized exclusively to astrocytes while CCL2 was also present in microglia. Despite the high levels of CXCL10 and CCL2, T cell infiltration was mild and no B cells were found. Thus, mutations in GFAP are sufficient to trigger a profound inflammatory response. The cellular stress caused by the accumulation of GFAP likely leads to the production of inflammatory molecules and microglial activation. Examination of human AxD CNS tissues also revealed microglial activation and T cell infiltrates. Therefore, the inflammatory environment may play an important role in producing the neuronal dysfunction and seizures of AxD.

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

“…Previous neuropathological investigations have described that lymphocytic infiltration or microglial activation was not massive in AxD brain [2,23]. Olanbarria et al investigated detailed alteration of the cytokine network in AxD model mice with both OE of human wild-type GFAP and heterozygous knock-in of mice Gfap R236H, and detected inflammatory response [24]. Consistent with this report, in our study, AxD astrocytes from patient iPSCs exhibited increased amounts of secreted GM-CSF, IL5, IL6, and TNFα.…”

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

“…Astrocytes display neurotoxic activities in the context of chronic CNS inflammation and also induce and amplify pathogenic activities in microglia and monocytes recruited to the CNS (40,(45)(46)(47)(48)(49)(50)(51). Thus, to evaluate the relevance to disease pathogenesis of the effects of FTY720 on the transcriptional program of astrocytes, we analyzed the effects of FTY720 on the neurotoxic potential of astrocytes and on their ability to control migration and monocyte polarization (2).…”

Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model

“…In the presence of an insult however, astrocytes amplify the inflammatory process that is initiated by microglia (Crotti and Glass, 2015;Saijo et al, 2009). The importance of (dysfunctional) astrocytes for the propagation of inflammation has been well demonstrated for distinct neurological diseases such as Alzheimer s, Alexander s and Huntingtons disease (Crotti and Glass, 2015;Olabarria et al, 2015;Zhang and Jiang, 2015). Astrocytes produce chemokines such as CXCL1, CCL2, CXCL10, or CCL11 that influence microglia reactivity Hennessy et al, 2015;Parajuli et al, 2015).…”