Abstract
The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as targets and mediators of endocannabinoid signaling in MS is poorly understood. Here we used a microfluidic RT-qPCR screen to assess changes in the expression of the main endocannabinoid signaling genes in astrocytes and microglia purified from female mice during the time-course of experimental autoimmune encephalomyelitis (EAE). We show that astrocytes and microglia upregulate the expression of genes encoding neurotoxic A1 and pro-inflammatory molecules at the acute disease with many of these transcripts remaining elevated during the recovery phase. Both cell populations exhibited an early onset decrease in the gene expression levels of 2-arachidonoylglycerol (2-AG) hydrolytic enzymes that persisted during EAE progression as well as cell-type-specific changes in the transcript levels for genes encoding cannabinoid receptors and molecules involved in anandamide (AEA) signaling. Our results demonstrate that astrocytes and microglia responses to autoimmune demyelination involve alterations in the expression of multiple endocannabinoid signaling-associated genes and suggest that this system may regulate the induction of neurotoxic and pro-inflammatory transcriptional programs in both cell types during MS.
Highlights
multiple sclerosis (MS) is regarded as a chronic demyelinating disease initiated by pathogenic autoimmune responses against myelin, followed by a broader inflammatory and neurodegenerative process [1]
To investigate the role of endocannabinoids in regulating astrocyte dysfunction in MS we analyzed the gene expression levels of the principal endocannabinoid signaling molecules in cells purified during EAE progression, using a microfluidic RT-qPCR screen
We measured increased levels of Napepld together with a marked reduction in Fabp7, these alterations were concomitant with augmented Faah transcripts (Figure 1B; Table S2)
Summary
MS is regarded as a chronic demyelinating disease initiated by pathogenic autoimmune responses against myelin, followed by a broader inflammatory and neurodegenerative process [1]. In EAE, reactive astrocytes promote inflammation and neurodegeneration through multiple mechanisms, which include neurotoxicity, the recruitment of inflammatory cells to the CNS, and the modulation of microglial responses [2,4,8] In this context, recent landmark studies have allowed the characterization of a population of neurotoxic astrocytes expressing complement component 3 (C3) in response to pro-inflammatory cytokines released by activated microglia [9]. Recent landmark studies have allowed the characterization of a population of neurotoxic astrocytes expressing complement component 3 (C3) in response to pro-inflammatory cytokines released by activated microglia [9] This subset of reactive astrocytes, termed A1, exhibit transcriptional programs destructive to synapses and oligodendrocytes and inhibitory to remyelination with potential pathogenic consequences in human MS and animal models of the disease [9,10,11]
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