Abstract
Astrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate in vivo that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited.
Highlights
Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by acute and chronic waves of inflammation causing demyelination and axonal loss, which clinically manifest as transient as well as accumulating neurological deficits
Since numerous studies have recently demonstrated the vast heterogeneity of astrocytes states in inflamed tissue [2, 4, 6, 8], we investigated whether Ptn expression was associated with certain astrocyte subtypes or activation states
Cluster 4, which showed the highest upregulation of PTN and was associated to a neurotrophic signature, was reduced 6.2-fold in MS patient samples compared to controls, indicating that there may be a loss of protective astrocyte functions during neuroinflammation (Supplementary Figures 1A, B)
Summary
Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by acute and chronic waves of inflammation causing demyelination and axonal loss, which clinically manifest as transient as well as accumulating neurological deficits. While our increasing understanding of peripheral immune cell activation and CNS infiltration has led to the development of efficient immune therapies targeting the initial stages of MS, mechanistic insight into the role of CNS-resident cell populations including astrocytes and microglia in chronic disease progression as well as their therapeutic potential have been limited [1, 2]. Based on their strategic location in the CNS and the multitude of interactions with CNS-resident and infiltrating cells, glial cells offer a hitherto neglected potential to target poorly treatable late stages of autoimmune CNS inflammation [3]. Pharmacological induction of these phenotypes and therapeutic exploitation of protective astrocyte-derived mediators is missing.
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