Reactive Astrocytes: Production, Function, and Therapeutic Potential

Abstract

Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions change in response to immune attack, chronic neurodegenerative disease, or acute trauma. In this review, we summarize recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of "reactive" astrocytes with strikingly different properties, one type being helpful and the other harmful. We will also discuss new methods for purifying and investigating reactive-astrocyte functions and provide an overview of new markers for delineating these different states of reactive astrocytes. The discovery that astrocytes have different types of reactive states has important implications for the development of new therapies for CNS injury and diseases.

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…Reactive astrocytes play a significant role in secondary injury in SCI, with "reactive astrocyte'' first described during the 1970s after discovery of GFAP [36], which is currently used as a routine identifier of astrocytes in the healthy CNS. Elevated GFAP level is considered a marker of astrocyte reactivity [37]. Numerous studies report that reactive astrocytes rather than a single type, are highly heterogeneous, and that neuroinflammation and ischemia can induce two different types of reactive astrocytes, "A1" and "A2," respectively.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Astrocytes in Alzheimer's disease show changes in glutamatergic and GABAergic signaling and recycling, potassium buffering, and in cholinergic, purinergic, and calcium signaling (Osborn, Kamphuis, Wadman, & Hol, 2016). Additionally, a subtype of reactive astrocytes is induced by activated neuroinflammatory microglia, which lose most normal astrocytic functions, but gain a neurotoxic function, and is abundant in various human neurodegenerative diseases including Alzheimer's (Liddelow & Barres, 2017). …”

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…Based on those findings, it was recently proposed that reactive astrocytes can be classified as A1 astrocytes, which secrete proinflammatory signals that are harmful to neurons, or A2 astrocytes, which, in turn, secrete neurotrophic factors that can promote survival and modulate inflammatory response. In fact, A1 astrocytes were induced in vivo by LPS-dependent microglia activation [66]. This activation profile leads these cells to secrete toxic factors as well as losing major trophic functions like synapse support and phagocytic capacity.…”

“…This activation profile leads these cells to secrete toxic factors as well as losing major trophic functions like synapse support and phagocytic capacity. Interestingly, A1 astrocytes seem to be specifically induced by three simultaneous microglia-derived signals: TNF-α, IL-1α, and C1q [66]. Thus, a possibility arises that different pools of cytokines secreted from activated microglia can potentially drive distinct astroglial responses, which in turn can affect the extension and phenotype of the lesion and also of the glial scar.…”

“…Astrocytes contribute to orchestrate chronic neuroinflammation in ALS, displaying a variety of phenotypic changes, with the potential to induce motor neuron apoptosis [66, 82, 98, 99]. Astrocytes are in direct contact with neurons, providing structural, metabolic, and trophic support, while actively participating in the modulation of neuronal excitability and neurotransmission [100].…”