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Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes the modes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neumaier, Rothhammer and Linnerbauer.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Linnerbauer, Lößlein, Farrenkopf, Vandrey, Tsaktanis, Naumann and Rothhammer.)

Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system., (Copyright © 2020 Linnerbauer and Rothhammer.)