The Dual Role of Astrocytes in CNS Homeostasis and Dysfunction

Abstract

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia.

1. Introduction

Astrocytes are a type of glial cell that is common in the central nervous system (CNS). They are easy to spot since they have a star shape. In the 19th century, scientists first recognized astrocytes, but they were thought to be just support cells for neurons. The blood–brain barrier consists of pericytes, endothelial cells, and astrocytes together they play several important roles, including keeping neurons stable, controlling the levels of neurotransmitters, changing the activity of synapses, and forming the blood–brain barrier. They also help with metabolic support, maintain ion balance, change immune responses, and help repair mechanisms after an injury to the central nervous system. Astrocytes communicate with neurons and other glial cells through complicated calcium signalling and the release of gliotransmitters. This directly affects synaptic plasticity and neurovascular coupling. The morphological subtypes of astrocytes are known as protoplasmic, fibrous, radial, velate, Bergmann, and interlaminar astrocytes. Whereas fibrous astrocytes are prevalent in white matter and have long, thin, less branched processes, protoplasmic astrocytes are star-shaped, densely branched cells found in grey matter. Müller cells in the retina and Bergmann glia in the cerebellum are examples of radial astrocytes that have long processes that extend across neural layers. Interlaminar astrocytes are common in primates and are identified by long processes that cross several cortical layers, while velate astrocytes are found in the olfactory bulb and cerebellum. In the central nervous system, these subtypes represent distinct forms, regional distributions, and specialized functions. Astrocytes change in reactive ways when there is neurodegenerative disease like AD and PD disease, which often exacerbates inflammation, neurodegeneration, and scar formation. Astrocytes are well-known as important regulators of CNS health and disease because they have several important jobs. This makes them a primary focus of modern neuroscience and pharmaceutical research. The astrocytes make up approximately 20% to 40% of the brain’s glial cell population and about 25% of total brain volume [1]. Histologically, these processes surround blood vessels and synapses, which is why they are often called the “neurovascular unit.” Astrocytes change the flow of blood in the brain and provide nutrients and oxygen based on the activity of neurons. They are important for keeping the extracellular environment stable, mainly by controlling the levels of ions like potassium and buffering neurotransmitters like glutamate [2].

A crucial element of astrocyte function is their involvement in “tripartite neurotransmission,” a conceptual model that reinterprets the synapse to include not only the presynaptic terminal, synaptic cleft, and postsynaptic terminal, but also the astrocytic processes that encase and sense neuronal signals. In this setting, alterations in astrocytic reactivity, exemplified by the increased expression of glial fibrillary acidic protein (GFAP), a characteristic of reactive astrocytes, may indicate continuing pathogenic or adaptive processes, including neuroinflammatory or degenerative changes [3]. Astrocytes and neurons originate from a shared neuroepithelial progenitor. These precursors have a gliogenic transition influenced by specific transcription factors governed by topographical and temporal considerations. It has been proposed that the topographical and temporal regulation of astrocyte development leads to astrocyte heterogeneity, which subsequently influences total brain patterning [3,4]. Recent single-cell RNA sequencing studies have uncovered astrocyte heterogeneity by identifying various transcriptomic subtypes with region-specific distributions in the adult mouse brain. Five molecularly distinct astrocyte subtypes were identified in the cortex and hippocampus, each characterized by unique gene signatures, including Slc1a3, Sox9, and Aldh1l1. Subtypes exhibiting progenitor-like and proliferative gene expression, such as Ascl1 and Hmgb2, were primarily identified in white matter regions, including the corpus callosum. In contrast, subtypes enriched in classical astrocyte genes (Gfap, S100a6) displayed unique spatial localization [4,5,6]. Astrocytes constitute the predominant glial cell type inside the central nervous system. In the cortex, the majority of astrocytes exhibit extensive ramification with delicate processes that collectively delineate the territory of a single astrocyte. In a healthy brain, neighbouring astrocytes do not overlap, creating a “tiled” brain structure characterized by astrocyte territories. Astrocytes are typically detected in immunohistological assays with antibodies against glial fibrillary acidic protein. Some astrocytes, especially in certain brain regions or specific phenotypic states, may express low or undetectable levels of GFAP [7]. Astrocytes and microglia participate in a dynamic interaction that regulates neuroinflammatory responses and neuronal well-being. In Alzheimer’s disease (AD), activated microglia secrete IL-1α, TNF, and C1q, transforming astrocytes into a neurotoxic A1 phenotype.

The A1/A2 classification of reactive astrocytes serves as an effective framework for differentiating astrocyte phenotypes in response to central nervous system injury and disease. A1 astrocytes are typically neurotoxic, generating pro-inflammatory molecules and neurotoxins that lead to neuronal death, frequently triggered by microglia-derived factors such as C1q, TNF-α, and IL-1α. A2 astrocytes, on the other hand, have a neuroprotective profile because they increase the levels of anti-inflammatory substances and neurotrophic factors that help neurons stay alive and repair tissue. This distinction has facilitated the comprehension of the dual functions of astrocytes in neuroinflammation and neurodegeneration, steering research towards therapeutic approaches designed to inhibit A1 or enhance A2 phenotypes for the treatment of CNS disorders [8,9,10]. A2 astrocytes are a type of neuroprotective cell that appears after an injury to the central nervous system. This is usually caused by microglial signalling. These cells release a number of neurotrophic factors and cytokines that help repair tissue and regrow axons while fighting inflammation. A2 astrocytes increase the levels of chemicals including GDNF, NF-E2-related factor 2, and prokineticin-2, which help neurones stay alive, grow, and change their synapses. Their activation protects mitochondria, sends signals that stop cell death, and lowers oxidative stress. This is different from the neurotoxic A1 subtype, which makes injury worse. These traits make A2 astrocytes important for protecting neurones in both acute and chronic neuropathologies. A1 astrocytes forfeit their homeostatic duties, including synaptic support and antioxidant defence, while acquiring neurotoxic characteristics that precipitate neuronal death. Recent studies underscore the intricacy of this connection. Astrocyte-derived IL-33 has been associated with the modulation of microglial phagocytic activity, especially in synaptic pruning during development [11,12,13,14].

2. The Role of AQP4 in Maintaining Water Homeostasis Within the Brain

Based on numerous discoveries indicating an interchange of solutes and water between the interstitial fluid (ISF) and cerebrospinal fluid (CSF), the possibility of a brain-specific tissue circulation was posited years ago and termed the “Glymphatic System” (GS) [15,16]. More recently, it has become increasingly apparent that the GS is necessary for the maintenance of a healthy brain. Abnormalities in the GS are related to the majority of neuro-pathologies [17]. Aquaporins (AQPs), which are essential for water transport across cell membranes, appear to be absent in brain capillary endothelial cells (BCECs). AQP 4 is localized in astrocytes, exhibiting significant polarization, since it is mainly situated at the endfeet that interface with the blood–brain barrier, within specialized structures known as orthogonal arrays of particles (OAPs) [18]. Microtubules, mitochondria, and intermediate filaments made of glial fibrillary acidic protein (GFAP) are some of the organelles that may be found in the astrocyte end foot, which are highly significant structures [19]. Due to its significance in physiological water transport across the blood–brain barrier, it is essential that AQP4 proteins are present at appropriate levels in astrocytes and, significantly, are accurately localized; both alterations in AQP4 expression and its mislocalization have been associated with pathology. Some studies shows AQP4-deficient mice exhibit markedly elevated brain water content when infused with artificial cerebrospinal fluid into the brain’s extracellular space [20] (Figure 1).

Furthermore, it has been indicated that the localization of AQP4 is contingent upon the proper organization of the astrocytic endfoot, which is, in turn, reliant on the assembly of gap junctions (GJs) formed by connexins 43 and 30 (Cx43 and Cx30, respectively) between the end feet; microhemorrhages are notably more prevalent in Cx43-deficient mice. Brain oedema has been observed in numerous pathological conditions, including cancer and stroke, with alterations in the production and/or localization of AQP4 frequently identified. The involvement of AQP4 in these changes indicates that this protein and its organization may serve as a therapeutic target [21].

Recently, a variant of AQP4 featuring a C-terminal extension (AQP4x) has been isolated, demonstrating its involvement in maintaining the integrity of the blood–brain barrier [22]. Conversely, endothelial cells exhibit expression of the autophagy-related seven gene (Atg7), which encodes an E1-like ubiquitin-activating enzyme that plays a role in autophagy [23]. Atg7 has recently been identified as a regulator of the interaction between astrocytic end feet and the basal membrane (BM), the extracellular structure facilitating communication among BCECs and other brain cells; notably, the dissociation of astrocytes from micro-vessels in the brain of a transgenic mouse with a conditional deletion of Atg7 in BCECs has been revealed. Notably, Atg7 regulates fibronectin expression, which appears essential for astrocyte attachment to the GM [24]. Two additional genes, whose expression is astrocytic and essential for astrocyte adhesion to the GM, are those that encode laminin and the laminin receptor [25,26]. Antibodies against aquaporin-4 (AQP4), especially AQP4-IgG, are very important in the autoimmune neurological disease neuromyelitis optica spectrum disorder (NMOSD). These antibodies attack the AQP4 water channel on astrocytes, which causes cell- and complement-mediated cytotoxicity, which in turn causes neuroinflammation and demyelination. Researchers have created new monoclonal antibodies, like “aquaporumab,” that stop pathogenic AQP4-IgG from binding to AQP4 without affecting the immune system. This protects astrocytes from damage without suppressing the immune system. In preclinical models, this competitive blockade has been shown to work by greatly lowering the number of lesions that form in tissues and animals. Also, researchers are looking into small-molecule inhibitors that can physically block the interaction between antibodies and AQP4. These advancements underscore the potential of AQP4 antibody-targeted therapies to specifically address NMOSD and possibly other astrocyte-associated disorders, signifying a transformative shift in the management of autoimmune neurological diseases [27,28,29,30].

Astrocyte–Microglia Interaction

The interaction between astrocytes and microglia is a dynamic and complex process that is very important for both healthy and diseased brains. These two types of glial cells talk to each other by touching, releasing signalling molecules, and exchanging extracellular vesicles. Together, they control responses that are important for neurogenesis, maintenance, and the modulation of neuroinflammation. Microglia have pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) that are very sensitive to damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). This makes them quickly switch to an activated, often pro-inflammatory (M1) phenotype. These activated microglia secrete cytokines such as TNF-α, IL-1α, and C1q, prompting astrocytes to assume a pro-inflammatory (A1) phenotype, thereby exacerbating neuroinflammation and compromising neuronal viability. Astrocytes can also phagocytose microglial fragments through receptors like Tyro3, Axl, and MerTK, especially when microglia are damaged. This shows that there is a reciprocal, compensatory relationship that helps keep the brain stable. Aside from inflammation, the interaction between astrocytes and microglia is crucial for synaptic pruning, tissue repair, and the integrity of the blood–brain barrier. Microglia remove synaptic debris, while astrocytes help form synapses and keep the neurovascular unit stable. In the context of chronic neuroinflammation or tissue injury, microglia can transition to an anti-inflammatory (M2) state and instruct astrocytes to assume an A2 phenotype. This is marked by the secretion of neuroprotective factors such as IL-10 and TGF-β, which mitigate inflammation and facilitate tissue repair. Furthermore, extracellular vesicles, including exosomes, facilitate glial communication, with astrocyte-derived exosomal microRNAs capable of regulating microglial activation pathways, as demonstrated by miR-873a-5p’s inhibition of NF-κB signalling in microglia. The equilibrium and timing of these intricate, bidirectional interactions determine the resolution or intensification of neuroinflammatory responses, affect disease progression in disorders such as Alzheimer’s and stroke, and signify potential therapeutic targets. Astrocyte–microglia crosstalk exemplifies the complex cellular interactions that are fundamental to CNS health and disease, providing essential insights for future neurotherapeutic strategies [31,32,33,34].

3. Role of Astrocyte in the Central Nervous System

The macroglia, which include astrocytes, oligodendrocytes, and ependymal cells, and the microglia are the two categories of glial cells that are found in the central nervous system (CNS). The astrocyte is the subject of this review essay. Astrocytes possess significant physiological features that are associated with the maintenance of homeostasis in the central nervous system [35,36,37]. The release of neurotrophic factors is one of the ways astrocytes influence neuronal function. Astrocytes also play a role in the growth of neurons, facilitate the metabolism of neurotransmitters, and regulate the levels of extracellular potassium and pH [38]. Astrocytes have lately been recognized for their dynamic involvement in the regulation of neuronal function [39,40], a role previously unknown. It has been demonstrated, for instance, that astrocytes are necessary for the preservation of synapses in vitro and that they enhance the number of mature functional synapses on neurons in the central nervous system. The findings of this study indicate that astrocytes may play an active role in synaptic plasticity. Similarly, the removal of reactive astrocytes results in a significant amount of neuronal degeneration in the central nervous system of an adult who has been damaged [41]. The blood–brain barrier (BBB) is a structure that serves to limit the entry of blood-borne materials into the central nervous system (CNS) [17,42,43] (Figure 2).

Astrocytes influence the creation and maintenance of the BBB structures. As a result of the fact that astrocyte foot processes are near the abluminal surface of the microvascular endothelium of the BBB in vivo, astrocytes contribute to the structural as well as the functional integrity of the BBB [44]. The research conducted by the researchers demonstrates the significance of astrocytes in this process. The researchers found that astrocyte ablation failed to repair the blood–brain barrier and prevent vasogenic oedema. Soluble factors released by astrocytes seem to contribute to the preservation of the BBB, potentially by facilitating the establishment of tight junctions among endothelial cells, although this has not been conclusively proven. Numerous well-defined molecules, such as Sonic Hedgehog (Shh), Angiopoietin-1 (ANG-1), retinoic acid (RA), Wnt growth factors, Insulin-like Growth Factor-1 (IGF-1), Glial cell line-derived Neurotrophic Factor (GDNF), Fibroblast Growth Factor (FGF), and Apolipoprotein E (ApoE), are thought to be essential in maintaining BBB integrity by enhancing tight junction formation, endothelial stability, and anti-inflammatory signalling [45,46]. This may be accomplished by stimulating the establishment of tight junctions between endothelial cells at some point. It has recently been demonstrated that endothelial cells can stimulate the differentiation of astrocyte precursor cells into astrocytes in vitro. This process is facilitated by the production of leukaemia inhibitory factor (LIF) by endothelial cells [47]. When it comes to the formation of the blood–brain barrier (BBB), it is possible that soluble substances from endothelial cells and astrocytes jointly contribute. The capacity of astrocytes to perform immunocompetent functions in the central nervous system is another significant characteristic of astrocytes that we investigate in this review. Before proceeding with this, a brief introduction to the molecules that are involved in immune responses is presented, along with a description of the process by which antigens are presented (see more about this below). This is then followed by a discussion of the function of astrocytes as immune effector cells, as well as how this may have an impact on some aspects of inflammation and immunological reactivity inside the brain [46,48,49,50].

3.1. Astrocyte Function in Healthy CNS

Astrocytes Are Multifunctional Glial Cells That Play Key Roles in Maintaining CNS Homeostasis

• Interaction with Synapse

• Uptake:

  ➢

  Ions like K⁺ and H₂O

  ➢

  Neurotransmitters: Glutamate, GABA, Glycine, D-serine

• Release:

  ➢

  Energy substrates (e.g., lactate)

  ➢

  Transmitter precursors (e.g., glutamine)

  ➢

  Neurotransmitters (e.g., glutamate)

  ➢

  Purines (ATP, adenosine)

  ➢

  Growth factors (e.g., BDNF, TNF-α)

  ➢

  Neurosteroids and other signalling molecules

• Interaction with the Node of Ranvier

• Provides energy substrates
• Other potential, less understood supportive functions

• Interaction with Blood Vessels

• Uptake:

  ➢

  Glucose and H₂O from blood

• Release:

  ➢

  Vasoactive agents:

  ▪

  PGE (Prostaglandin E), NO (Nitric Oxide)—cause dilation

  ▪

  AA (Arachidonic Acid)—causes contraction

• Gap Junction Communication

• Transfers ions like K⁺ and Ca²⁺ between astrocytes for buffering and signalling [51].

3.2. Astrocytes and BBB Formation and Maintenance

Astrocytes are star-shaped glial cells that are important for both building and keeping the blood–brain barrier (BBB) in good shape. The BBB is a very important barrier that controls the flow of substances between the blood and the central nervous system (CNS). They closely interact with endothelial cells, pericytes, and neurons in the neurovascular unit (NVU), which allows for strict control of the BBB’s structure and function [51,52,53]. Astrocytes help the BBB mature during the development of the CNS. In vitro and transplantation studies show that astrocytes make brain endothelial cells (BECs) have BBB properties. Astrocytes secrete soluble factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2), retinoic acid, and Wnt growth factors, which induce endothelial cells to enhance junctional integrity and decrease paracellular permeability. These astrocytic signals make tight junction proteins like claudins and ZO-1 increase the expression of these substances. which makes the BBB better restricts passage of substances, since stronger tight junctions tighten the BBB barrier [52,53,54,55]. Astrocytes are important for keeping the BBB stable and making small changes to it throughout adulthood. Their endfeet surround blood vessels in the brain and release trophic factors like Sonic Hedgehog (SHh), angiopoietin-1, apolipoprotein E, and transforming growth factor-beta (TGFβ). These factors strengthen tight junctions and keep the environment stable so that neurons can work properly. Astrocyte-specific proteins, such as sodium-bicarbonate cotransporter 1 (Slc4a4), help keep the pH and ion levels stable, which helps keep the BBB strong. Astrocytes also change the flow of blood in the brain and the balance of osmotic pressure, which affects the exchange of nutrients and waste across the BBB [56,57,58].

3.3. Astrocytes Control the Formation of Functional Synapses

Astrocytes release proteins known as thrombospondins (TSP) that stimulate neurons to establish synapses. Mature astrocytes in the uninjured adult brain typically do not express or release thrombospondins at significant levels. The major wave of thrombospondin (TSP) secretion and TSP-induced synaptogenesis occurs during developmental windows when astrocytes are still immature [59]. Cholesterol released by astrocytes significantly augments the presynaptic functionality of these synapses. The postsynaptic function of synapses, influenced by the quantity of synaptic AMPA glutamate receptors and Astrocyte-secreted proteins such as glypican 4/6, Chordin-like 1 (Chrdl1), pentraxin 3 (PTX3), and TNF-α are known to increase the abundance of postsynaptic AMPA receptors and modulate postsynaptic function at excitatory synapses [12,59]. Astrocytes facilitate synapse elimination by releasing an undiscovered signal that prompts neurons, and potentially microglia, to express and release C1q, which localizes at synapses and activates the classical complement cascade [60,61,62,63].

3.4. Astrocyte in Sleep

Astrocytes have a very important and varied role in controlling sleep. They affect sleep architecture, homeostasis, and quality in many different ways. These star-shaped glial cells interact with neurons and other brain cells in a dynamic way, changing the balance of neurotransmitters and ions, the flow of blood to the brain, and the signalling pathways that are important for sleep-wake cycles [64]. One important job of astrocytes is to release adenosine, which is a neuromodulator that comes from ATP metabolism. Adenosine makes you sleepy by activating inhibitory A1 receptors on neurons and lowering their excitability. Astrocyte intracellular calcium (Ca²⁺) signalling is fundamental to their function in sleep regulation, serving as an integrator of neuronal arousal signals and initiating the release of sleep-promoting substances such as adenosine and lactate. Calcium activity in astrocytes varies with sleep states and rises with sleep deprivation, highlighting its role in encoding sleep necessity and facilitating recovery sleep [65,66] (Figure 3).

Astrocytes also play a role in the glymphatic system, which helps the brain get rid of waste while you sleep. This helps sleep do its restorative work and may even protect against neurodegenerative diseases. Astrocytes also control the size and makeup of the extracellular space, which affects how easily neurons fire and how well synapses work, both of which are important for sleep modulation. Sleep deprivation influences astrocytic gene expression and morphology, underscoring their adaptive response to modified sleep states. Recent studies underscore that astrocytic calcium signalling in particular brain regions, including the basal forebrain, regulates both non-REM and REM sleep by affecting local neural circuits and inhibitory neurons. The evolutionary preservation of astrocytic sleep mechanisms in both mammalian and invertebrate species underscores their essential function in sleep regulation [65,66,67,68] (Figure 4a,b).

4. Role of Astrocytes in Diseased Conditions

4.1. Role of Astrocytes in Parkinson’s Disease

The presentation of Parkinson’s disease is multifaceted, potentially arising from trauma, infection, neuroinflammation, vascular abnormalities, genetic alterations, and other factors. In Parkinson’s disease (PD), a neurodegenerative disorder, dopamine neurones in the substantia pars compacta (SNpc) are diminished. Bradykinesia, rigidity and rest tremor are its hallmarks. Astrocytes are known to undergo the metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a synthetic heroin analogue, by monoamine oxidase-B (MAO-B). This pathway has been identified as the primary mechanism for dopamine-specific cell damage and MPTP bioactivation, which leads to Parkinsonian-like symptoms [69]. Nevertheless, other research has also mentioned astrocytic neuroprotection during MPTP exposure. The enhanced staining of glial fibrillary acidic protein (GFAP), an astrocytic marker, in the striatum serves as an example of this protection [70]. GFAP (Glial Fibrillary Acidic Protein) upregulation in the substantia nigra in Parkinson’s disease is reported. Some studies have found increased GFAP expression and reactive astrogliosis in regions of the substantia nigra with severe neuronal loss. However, other studies show only mild or even absent GFAP upregulation in the substantia nigra of PD [67,71].

Additionally, the SNpc of PD postmortem cases has been shown to have higher levels of astrocytes and GFAP positivity [71,72]. Notably, a recent study also demonstrated that GFAP-expressing astrocytes are the only cells that exhibit a-synuclein staining, a key component of Lewy bodies and Lewy neurites that are seen in the postmortem brain of PD [73,74]. By secreting various neurotrophic factors, including brain-derived neurotrophic factor (BDNF), glial cell-line-derived neurotrophic factor (GDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF), along with a variety of antioxidants, astrocytes have a neuroprotective effect on dopaminergic neurons [75,76,77]. In midbrain neuronal/glial cultures, dopaminergic neurons are protected by the release of neurotrophic factors from astrocytes [78,79]. Additionally, astrocytes may scavenge reactive oxygen species (ROS). Astrocytic MAO-B or catechol-O-methyl transferase (COMT) can metabolize dopamine produced from neurons, and glutathione peroxidase (GPX) removes the resulting free radicals [80] (Figure 5).

Furthermore, it has been demonstrated that elevated levels of GPX mediate the neuroprotective impact of astrocytic protease-activated receptor-1 (PAR-1) overexpression in Parkinson’s disease [81]. Neuronal cell death in Parkinson’s disease is linked to elevated oxidative stress [82]. The transcription factor known as NF-E2-related factor (Nrf2) attaches itself to the antioxidant response element (ARE), a DNA consensus sequence, and starts the transcription of genes that encode phase II detoxication enzymes and other components necessary for neuronal survival in oxidative stress [83,84]. According to recent research, neuroprotection in the MPTP model is mediated by Nrf2 expression that is specific to astrocytes [85]. Therefore, altering the Nrf2-ARE pathway in astrocytes may be a viable therapeutic approach for the management of Parkinson’s disease.

4.2. Role of Astrocytes in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurological condition and the predominant kind of dementia in advanced age. Alzheimer’s disease is characterized by the gradual decline of cognitive abilities, including memory and mental thinking [86]. Histopathological characteristics of Alzheimer’s disease (AD) encompass substantial extracellular senile plaques (SPs) formed by amyloid-beta (Aβ) aggregates and neurofibrillary tangles, which are intracellular deposits of hyperphosphorylated tau protein in specific brain areas [87,88]. Amyloid-beta is a peptide consisting of 42 amino acid residues generated through the selective proteolytic cleavage of transmembrane amyloid precursor proteins (APP) by beta- and gamma-secretases [85,86,88]. Some research finding suggest that the morphological characterization of GFAP-positive Astroglial cells in an Alzheimer’s disease mouse model at various ages demonstrated an age-dependent decline in GFAP expression [89,90,91]. The authors proposed that in an Alzheimer’s disease transgenic model, reactive hypertrophic astrocytes encircle the neurotic plaques. However, Astroglial cells in other cerebral regions experience atrophy, thereby explaining the initial alterations in synaptic plasticity and cognitive deficits associated with Alzheimer’s disease. In Alzheimer’s disease human tissue, significant astrogliosis is observed in cells adjacent to amyloid plaques, where activated astrocytes accumulate substantial quantities of Ab42, originating from neuronal debris and linked to the plaques [92,93]. The two dominant forms of Aβ are Aβ40 and Aβ42, with Aβ42 being more prone to aggregation and closely linked to Alzheimer’s disease pathology. Astrogliosis is a process that occurs in astrocytes, characterized by the proliferation of astrocytes, changes in their morphology, and an increase in the production of glial fibrillary acidic protein (GFAP). This process is a frequent characteristic of many neurodegenerative illnesses [94]. It is possible to interpret astrogliosis as either a helpful event for the promotion of neuronal survival through the synthesis of growth factors and neurotrophins that support neuronal growth or as a harmful event for neuronal function through the formation of glial scars, depending on the context of the disease.

Furthermore, astrocytes from individuals with dementia have markedly reduced complexity in comparison to those in a healthy brain. In the 3xTg-AD transgenic animal model, which closely mimics human Alzheimer’s disease pathology, astrocytes exhibit reactive enlargement around the neuritic plaques, but, across the brain parenchyma, astrocytes experience atrophy [91,94]. Astrocytes serve a crucial protective function in Alzheimer’s disease. Microglial cells are the primary agents in the creation of senile plaques. In contrast, astrocytes play a vital role in plaque destruction, as demonstrated by the ultrastructural three-dimensional reconstruction of human classical plaques at various developmental stages [95,96]. Astrocytes selectively internalize Amyloid-beta peptides, and the hypertrophic processes of astrocytes destroy Amyloid-beta -containing plaques [97], thereby inhibiting the accumulation of extracellular Amyloid-beta deposits [98]. The exact process by which astrocytes identify and eliminate Amyloid-beta remains unclear; however, apolipoprotein E (ApoE), primarily expressed in astrocytes, has been suggested to facilitate this cellular function. ApoE is crucial for astrocytes to chemically attract, internalize, and destroy amyloid-beta plaques in brain sections in vitro [99]. Astrocytes additionally have protective benefits in Alzheimer’s disease by suppressing active microglia. Astrocyte-derived TGF-β generated by Amyloid-beta may inhibit the activity of inducible nitric oxide synthase (iNOS) in microglia [100] (Figure 6).

Furthermore, astrocyte-conditioned media derived from proliferative cells inhibit activated microglia’s nitric oxide generation and the phagocytosis of SP cores [101]. The inability of astrocytes to effectively digest Amyloid-beta leads to the accumulation of Amyloid-beta -laden neuronal debris within astrocytes and the formation of astrocytic plaques [93]. Furthermore, astrocytes are stimulated by accumulating Amyloid-beta and generate inflammatory mediators, including interleukin 1b (IL-1b) and tumour necrosis factor-a (TNF-a), which may lead to neuronal damage [102]. Antibody-induced TNF-alpha enhances calcium-dependent glutamate release, perhaps resulting in neuronal death in Alzheimer’s disease [103]. Oxidative stress is associated with Amyloid-beta toxicity, as Amyloid-beta induces ROS generation and reduces GSH levels in these cells [104]. Furthermore, Amyloid-beta disrupts glucose metabolism in astrocytes, resulting in compromised neuronal survival [105].

4.3. Role of Astrocytes in Ischemia

Brain ischemia begins when cerebral arteries are persistently obstructed by events such as cardiac arrest, ischemic stroke, or traumatic brain injury, leading to disrupted cerebral blood flow, oxygen and glucose deprivation, impaired ATP production, ion imbalance, excitotoxicity, and subsequent neuronal injury. One of the most noticeable and early reactions to anoxia-ischemia is astrocyte inflammation [106]. Additionally, the cytoplasm of these astrocytes has rougher endoplasmic reticulum and mitochondria, and the nuclei are larger and paler [107]. It is well recognized that astrocytes play a crucial role in the pathogenesis of ischemia [108]. However, little is known about how they react after a stroke and how they contribute to neuroprotection. Glial scar formation during ischemia severely impairs functional recovery and regeneration processes [109] (Figure 7).

Furthermore, focal cerebral ischemia leads to elevated intracerebral pressure and astrocytic oedema, significantly exacerbating the ischemic episode [110]. Additionally, astrocyte enlargement may decrease glutamate absorption and release, which could initiate excitotoxicity [108]. Astrocytic gap junction channels, which are tiny holes that regulate homeostasis, are known to play a role in mediating brain injury in ischemic situations by distributing calcium ions and proapoptotic chemicals to nearby healthy cells [110,111]. The induction of spreading depression, which has been linked to infarct expansion, may also be facilitated by these gap junctions [112,113]. Notably, in the persistent focal ischemia model, rats given gap junction blockers such as octanol and halothane show decreased infarct volume and neuronal death [114]. One of the main astrocyte proteins that forms gap junctions, connexin43 (Cx43), is linked to defence against ischemic injury [115]. Mice with astrocytes deficient in Cx43 exhibited a much larger infarct volume along with enhanced apoptosis and inflammatory response [116,117,118]. Conversely, it has been demonstrated that astrocytes are important for regeneration in the long-term following injury. Astrocytes help neurons by secreting several neurotrophic and neuroprotective substances, regulating ion and water balance, and scavenging transmitters produced during synaptic activity. Numerous studies also support the idea that astrocytes protect neurons from oxidative stress through a mechanism that is dependent on GSH [116,117]. Following ischemia, cortical infarction and oedema are increased when GSH production is inhibited [119,120]. Moreover, in a forebrain ischemia model, the loss of CA1 hippocampus neurons is considerably decreased by astrocyte-targeted overexpression of heat shock protein 72 (Hsp72) or superoxide dismutase 2 (SOD2) [121]. Astrocytes can both shield neurons from ischemia and prolong neuronal injury. Thus, in order to offer important insight into possible treatments, future research targeted at comprehending their underlying mechanisms during ischemia is required. Glial scar formation during ischemia severely impairs functional recovery and regeneration processes [109]. Additionally, focal cerebral ischemia causes an increase in intracerebral pressure and astrocytic swelling, which intensifies the ischemic event considerably [110]. Additionally, astrocyte swelling may decrease glutamate absorption and release, which could result in excitotoxicity [108].

4.4. Astrocyte in Multiple Sclerosis

There is widespread astrocyte reactivity in the vicinity of acute inflammatory lesions. From slightly enlarged process-bearing cells in healthy neighbouring white matter to hypertrophic astrocytes at the lesion’s core, a spectrum of reaction is seen. As lesions mature, GFAP immunoreactivity rises, oedema falls, and hypertrophic astrocytes not only endure but also start to form bundles of glial filaments. Recent astrocyte mitotic activity, astroglial reactivity (especially at lesion margins), and recurring inflammatory activity are all linked to relapsing disease activity [122]. According to research on experimental autoimmune encephalomyelitis (EAE), astrocyte activation and endfeet loss around tiny blood arteries are early lesion formation events that are connected to perivascular oedema, following CNS inflammation, and a loss of BBB function [122] (Figure 8).

It is widely acknowledged that substances secreted by astrocytes are essential for the creation and maintenance of endothelial cells that constitute the blood–brain barrier (BBB). For instance, the activation of astrocytes by macrophage-derived IL-1 induces hypoxia-inducible factor-1 (HIF-1) and its target, vascular endothelial growth factor A (VEGF-A), in astrocytes. This, in turn, affects endothelial cells, leading to the down-regulation or loss of tight junction proteins claudin-5 (CLN5) and occludin, resulting in localized dysfunction of the blood–brain barrier (BBB) in damaged tissue, a process mediated by eNOS [123]. The inactivation of VEGF-A expression or the systemic selective inhibition of eNOS mitigates blood–brain barrier breakdown, diminishes lymphocyte infiltration and tissue damage, and safeguards against neurological deficits in experimental autoimmune encephalomyelitis (EAE) [124]. In addition to the tight connections on endothelial cells, astrocyte endfeet that constitute glia offer an extra barrier against autoreactive cellular activity in the central nervous system. Moreover, the disproportionate overexpression of matrix metalloproteinases (MMPs) in astrocytes and macrophages, in contrast to the stable expression or reduction of parenchymal basal membrane components, facilitates the dispersion of encephalitogenic cells into the central nervous system (CNS) [125]. It should be mentioned, too, that depending on the circumstances and the kind of MMP involved, extracellular matrix (ECM) remodelling can have both positive and negative effects. It is crucial to highlight the dual function of astrocytes, which includes fostering a permissive environment that encourages remyelination and assisting in axonal degeneration and demyelination. Therefore, a variety of factors, such as the type of lesion, the surrounding microenvironment, the timing of the injury, the interaction with other cell types, and factors influencing their activation, will determine the specific impact of astrocytes on the pathogenesis and repair of an inflammatory process [125].

4.5. Astrocyte in Amyotrophic Lateral Sclerosis (ALS)

In most of cases the etiology of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness that affects both the CNS’s upper and lower motor neurons is unknown. The illness often first manifests in midlife and causes gradual muscular paralysis, with a two-to-five-year survival rate. The gradual degradation of motor neurons in the brain stem, spinal cord, and motor cortex is a hallmark of amyotrophic lateral sclerosis (ALS). Although the exact chemical mechanism behind the gradual degeneration of motor neurons is unknown, it involves a process that is not cell autonomous. Astrogliosis is a reactive phenotype that astrocytes take on in response to acute injury or degenerative illnesses. The intricate reorganization of astrocyte biology known as astrogliosis reflects a range of possible phenotypes that impact neuronal survival and function in a way that is injury-specific. Reactive astrocytes are a major contributor to the pathophysiology of ALS patients, encircling both upper and lower degenerating motor neurons. Astrocytes are a key player in the pathophysiology of ALS. Astrocytes can affect the fate of motor neurons and the course of the disease by causing a loss of normal function or the acquisition of new traits. ALS-astrocytes can cause motor neuron death by secreting soluble substances or factors, according to the usage of several cell culture models. Since astrocytes are essential to the pathophysiology of ALS, treatments that alter astrocyte biology may aid in the creation of comprehensive therapeutic strategies to stop the disease’s progression [126] (Figure 9).

According to their location in the central nervous system (cortical or spinal astrocytes) and stage of the disease (pre-symptomatic and symptomatic), astrocytes in ALS are known to exhibit an abnormal and reactive profile, displaying distinct astrocytic markers. GFAP, vimentin, glutamate transporters, and NF-κB are all downregulated in the pre-symptomatic stage of cortical astrocyte proliferation, while S100B and Cx43 are upregulated [127,128]. Cortical astrocytes are more proliferative during the disease’s symptomatic stage, with decreased glutamate transporter and GFAP expression along with increased expression of NF-κB, HMGB1, S100B, and Cx43 [128,129]. While astrocytes in the symptomatic stage display a proliferative profile with increased expression of NF-κB, S100B, HMGB1, and Cx43, spinal astrocytes in the pre-symptomatic stage show lower expression of GFAP, S100B, and HMGB1. Depending on the model, situation, or research region, it has been demonstrated that the expression of GFAP in the symptomatic spinal astrocyte either increases or decreases [128,130]. These findings collectively show that astrocytes in ALS are highly diverse and heterogeneous.

4.6. Astrocyte in Epilepsy

Astrocytes are very important in the development and progression of epilepsy because they use many different ways to disrupt normal neural homeostasis, which leads to hyperexcitability and seizures. One of the primary functions of astrocytes is to keep the balance of ions outside of cells, especially by buffering potassium (K⁺) in space. In epilepsy, compromised gap junction coupling among astrocytes diminishes their capacity to redistribute surplus K⁺ released by hyperactive neurons, resulting in increased extracellular K⁺ concentrations that heighten neuronal excitability and facilitate seizures [131]. Astrocytes also control glutamate, which is the brain’s main excitatory neurotransmitter. In epileptic tissue, the expression and function of astrocytic glutamate transporters and glutamine synthetase are frequently reduced, leading to the accumulation of extracellular glutamate, which intensifies excitotoxicity and increases seizure susceptibility. Astrocytes also affect inhibitory neurotransmission by changing the levels of adenosine outside of cells through the enzyme adenosine kinase. When adenosine kinase levels go up in epilepsy, adenosine levels go down outside of cells, which makes excitatory synaptic transmission less effective, which makes hyperexcitability worse [132]. Astrocytes are important for neuroinflammation in epilepsy, in addition to keeping neurotransmitters and ions in balance. Reactive astrocytes secrete pro-inflammatory cytokines, including interleukin-1β, tumour necrosis factor-α, and chemokines, which amplify local inflammation, alter neuronal excitability, and promote seizure propagation. In seizures, the blood–brain barrier is broken down, allowing serum proteins and immune cells to enter the brain. These cells activate astrocytes, which causes transcriptional changes that downregulate potassium channels, glutamate transporters, and gap junction proteins. This makes the network less stable. In certain models, reactive astrocytes aberrantly synthesize and secrete gamma-aminobutyric acid (GABA) through non-synaptic pathways, potentially fulfilling a compensatory inhibitory function by activating tonic GABA receptors and mitigating interneuron loss in epileptic tissue [132,133,134,135] (Figure 10).

5. Key Signalling Pathways and Molecular Target

The primary goal of neuroprotective and anti-neuroinflammatory treatments targeting astrocytes is to prevent negatively activated cells, such as A1 astrocytes and disease-associated astrocytes, from secreting proinflammatory mediators and cytotoxins [50,136]. Well-defined targets for these interventions encompass toll-like receptors (TLR), TLR2, TLR3, TLR4, and the receptor for advanced glycation end products (RAGE), which interact with various molecules associated with cellular damage and pathology, including amyloid beta protein, α-synuclein, and high mobility group box 1 (HMGB1). The activation of these receptors primarily activates signalling pathways that result in the release of proinflammatory mediators and cytotoxins; consequently, TLR4 and RAGE antagonists, along with the astrocyte-specific deletion of these receptors, have been proposed as therapeutic approaches for neuroinflammatory disorders marked by astrocyte immune activation [137,138]. An adjunctive technique entails enhancing the anti-inflammatory and neuroprotective functions of astrocytes. Below are a few examples of recently found chemicals and mechanisms that can affect astrocyte neuroimmune functions (Figure 11). Apart from that.

The kynurenine pathway (KP) is the main way that tryptophan degrades in the brain. It is very important for both normal astrocyte biology and the development of central nervous system (CNS) pathology. Astrocytes are the main non-neuronal cells that control neurochemical signalling and keep the CNS in balance. They also have a unique pattern of KP enzyme expression. Microglia and infiltrating macrophages can make neurotoxic quinolinic acid (QUIN), but astrocytes mostly turn tryptophan into kynurenic acid (KYNA), a molecule that protects neurons by blocking NMDA receptors and stopping glutamatergic excitotoxicity. This balance shows that they usually protect neurons when the body is healthy. Astrocytes do not have a lot of kynurenine 3-monooxygenase (KMO), which is the enzyme that changes kynurenine into 3-hydroxykynurenine. This means that local QUIN production is kept to a minimum. Astrocytes are still very sensitive to inflammatory cytokines like interferon-γ, tumour necrosis factor-α, and interleukin-1. These cytokines cause indoleamine 2,3-dioxygenase (IDO-1) expression and start KP activation during neuroinflammation [139,140,141].

In disease, particularly neurodegenerative disorders and neuroinflammatory conditions such as multiple sclerosis (MS) and Alzheimer’s disease (AD), astrocytic activation of the kynurenine pathway (KP) functions as a double-edged sword. Pathological activation results in elevated synthesis of kynurenine and KYNA, while simultaneously generating substrates for adjacent microglia and infiltrating immune cells, which can subsequently transform kynurenine into neurotoxic QUIN owing to their enhanced KMO activity. This process worsens excitotoxic neuronal death, glial cell dysfunction, and promotes demyelination, which makes the disease worse. Cytokines from astrocytes and KP metabolites also help chronic inflammation, astrogliosis, changes in chemokine signalling, and changes in the cytoskeleton, which makes neurological problems like MS and AD worse. Furthermore, KP metabolite levels exhibit a strong correlation with clinical severity and relapse in multiple sclerosis (MS), acting as potential biomarkers and elucidating unique disease mechanisms across central nervous system (CNS) disorders [142]. The KP in astrocytes modulates glutamatergic neurotransmission and excitotoxicity, and it also affects other areas of CNS biology, such as energy metabolism by making NAD+, immune regulation by depleting TRP and killing T cells, and keeping the blood–brain barrier intact. Interactions among astrocytes, microglia, monocytes, and other resident brain cells exacerbate KP dysregulation; for instance, astrocytes provide surplus kynurenine that invading immune cells utilize to promote QUIN accumulation, thereby increasing neurotoxicity. The breakdown of the blood–brain barrier in pathology allows more immune cells to enter the brain, which increases KP activation and causes more problems with astrocytes’ metabolism and signalling [139].

5.1. Glucagon-like Peptide 1 (GLP-1)

Most people know GLP-1 as a hormone that comes from cells in the intestines and makes pancreatic β cells make and release insulin. GLP-1 may easily pass the blood–brain barrier, and CNS cells can also make it. GLP-1 has been shown to have neuroimmunomodulatory actions that affect the brain cells’ metabolism. GLP-1 receptors (GLP1R) are found in astrocytes in humans, mice, and rats. GLP-1 stops LPS-stimulated cultured rat astrocytes from releasing IL-1β, while liraglutide, a GLP-1 mimic, stops cultured rat astrocytes that have been exposed to advanced glycation end products (AGEs) from releasing IL-1β and TNF [143]. Exenatide, a GLP1R agonist, increases the amount of glutathione peroxidase in human astrocytes, which makes them better at fighting free radicals [142,143,144]. GLP1R agonists can prevent the conversion of murine astrocytes to the A1 phenotype, which is brought on by microglia stimulated with α-synuclein fibrils, in addition to inhibiting proinflammatory activation of murine microglia and inducing their production of nerve growth factor (NGF) [145] and brain-derived neurotrophic factor (BDNF) [146,147]. In addition to being licensed for the treatment of type 2 diabetes mellitus, GLP-1 receptor agonists with extended biological half-lives have demonstrated encouraging protective benefits in preclinical animal models and the early clinical trials of AD and PD. The positive effects of GLP1R agonists on astrocytes may account for some of their neuroprotective properties [148].

5.2. αB-Crystallin

A heat-shock protein called αB-Crystallin is increased in glial cells linked to several neurological conditions. Stressed cells may discharge it into the extracellular space. Although it may also interact with TLR1 and CD14, αB-Crystallin is an agonist of TLR2. It has been demonstrated to control glial immunological activities [149,150,151]. Using mice with experimental autoimmune encephalomyelitis (EAE) as models for human multiple sclerosis, Guo et al. show that αB-crystallin is preferentially expressed in spinal cord astrocytes and significantly upregulated in these astrocytes. LPS-stimulated U251 astrocytic cells and murine BV-2 microglia significantly reduce their production of IL-1β and IL-6 after pretreatment with 50 ng/mL recombinant αB-crystallin. Research finding by Hampton et al. show that astrocytes respond to αB-crystallin stimulation by boosting the expression of several neuroprotective factors, such as leukaemia inhibitory factor (LIF), NGF, and BDNF, using glial cells isolated from postmortem human brains. However, this activation necessitates the presence of soluble factors released by αB-crystallin-stimulated microglia. Therefore, αB-crystallin can be employed to trigger the release of neuroprotective chemicals from astrocytes and control their immunological functions. In several animal models of neuroinflammation, such as EAE, stroke, spinal cord injury, and tauopathies, in vivo treatment of this protein provides protection. It is interesting to note that this protein has already been administered intravenously in a multiple sclerosis clinical trial with no significant side effects [149,150,151].

5.3. Toll-like Receptor (TLR)3

TLR3 can identify human messenger RNA (mRNA) and mRNA-protein complexes in addition to sensing viral double-stranded RNA. Numerous inflammatory stimuli cause astrocytes to upregulate TLR3 [152] selectively. However, astrocyte TLR3 stimulation activates parallel intracellular signalling pathways that result in the release of pro- and anti-inflammatory molecules [153]. Numerous studies have emphasized the comprehensive neuroprotective function of TLR3 activation in astrocytes. Consequently, the stimulation of adult human astrocytes with a TLR3 agonist, polyinosine: polycytidylic acid (Poly I: C), elevates the expression of several growth factors (neurotrophin-4, LIF, BDNF) and the anti-inflammatory cytokine IL-10, resulting in improved neuronal survival in organotypic human brain slice cultures. Poly (I: C) has been demonstrated to stimulate the expression of glial cell-line-derived neurotrophic factor (GDNF) in murine astrocytes, which can be further augmented through differential modulation of astrocyte eicosanoid receptor subtypes [154]. Intraperitoneal Poly (I: C) exhibits neuroprotection in a rat model of localized cerebral ischemia by diminishing infarct volume and suppressing astrocyte activation, as evaluated by glial fibrillary acidic protein (GFAP) expression [155]. The study indicates that Poly (I: C) enhances TLR3 expression and the release of anti-inflammatory interferon (IFN)-β in astrocytes, while simultaneously suppressing proinflammatory IL-6 in cultured rat astrocytes subjected to oxygen–glucose deprivation/reoxygenation. Consequently, TLR3 agonists can be employed to elicit a neuroprotective phenotype in astrocytes [154].

5.4. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Studies showing variations of this gene linked to an increased risk of several neuroinflammatory illnesses, such as AD, PD, and frontotemporal dementia, have elevated TREM2 to the forefront of neuroimmunological study. Apolipoprotein E, which is linked to the pathophysiology of AD, and damage-associated lipids are detected by this transmembrane receptor. Although TREM2 is mainly expressed by microglia in the brain, it has also been found in human and murine astrocytes. In several animal models of neurodegenerative illnesses, such as AD, PD, and multiple sclerosis, overexpression of TREM2 has positive effects [155,156]. Rosciszewski et al. Exhibit TLR4-dependent proinflammatory activation of murine astrocytes, quantified by nuclear factor (NF)-κB activation and elevated production of IL-1β and TNF; stimulation of astrocyte TREM2 mitigates this activation [157,158]. Intranasal delivery of the TREM2 ligand COG1410, an apolipoprotein E mimic, mitigates neuroinflammation in a murine model of intracerebral haemorrhage, notably reducing brain concentrations of IL-1β and TNF [157]. Although the effects of COG1410 on astrocytes are not evaluated in this investigation, diminished quantities of GFAP-positive astrocytes have been documented following intravenous administration of COG1410 in rats subjected to cortical contusion injury [159]. Significantly, improved cognitive decline has been observed in ageing mice with astrocyte-specific downregulation of TREM2, which appears to contradict the previously reported favourable effects of TREM2 stimulation in astrocytes [160]. Although additional research is required to comprehensively elucidate the consequences of TREM2 activation on astrocyte immunological activities, this receptor may be regarded as a candidate for the development of neuroprotective therapies (

Table 1. Presumed effects of exposure of GLP-1, αB-Crystallin, mRNA, Poly (I: C) on brain glial cells.

Receptors	Cell Types Expressing the Receptor	Receptor Agonist	Effect of Immune-Activated Astrocytes	Protective Function of Induced Astrocytes	References
GLPR1	Astrocytes Microglia Neuron	GLP-1, exenatide, liraglutide	Inhibit IL-1β and TNF	Upregulate glutathione peroxidase	[144,145,147]
TLR2, TLR1, CD14	Astrocytes Microglia Neuron	αB-Crystallin	Inhibit IL-1β and IL-6	Upregulate LIF, NGF, BDNF	[149,151]
TLR3	Astrocytes Microglia Neuron	mRNA, Poly (I: C)	Inhibit IL-6, downregulate GFAP	Upregulate neurotrophin-4, LIF, BDNF, GDNF, IL-10, IFN-β	[154,155]
TREM2	Astrocytes Microglia Neuron	Lipids, apolipoprotein E, COG1410	Inhibit IL-1β and TNF, downregulate GFAP	Not determined	[159]

).

6. Conclusions

Astrocytes are increasingly recognized as pivotal regulators of central nervous system function and dysfunction. Their ability to sustain homeostasis, regulate synaptic function, establish and maintain the blood–brain barrier, and influence immunological responses renders them essential for both CNS health and disease mechanisms. The dual character of astrocytic responses—either protective or harmful depending on the illness context and stage—poses both a difficulty and an opportunity for therapeutic intervention. Progress in comprehending astrocyte-specific mechanisms, reactive phenotypes (e.g., A1 neurotoxic versus A2 neuroprotective), and astrocyte-microglia interactions offers significant avenues for further investigation. Focusing on astrocyte-mediated processes presents significant potential for alleviating neuroinflammation and enhancing neuro-regeneration across many CNS diseases.