Table 1.
Neurotoxic and neurotrophic mediators associated with astrocytes.
| Mediator | Brain Expression * |
Physiological Roles ** | Neuropathological Roles | Model/Astrocyte Description *** | Refs. |
|---|---|---|---|---|---|
| Neurotoxic mediators | |||||
| CD49f | TH, 25; HY, 20.9; MO, 20.8; SC, 20.5; CTX, 20.3. | Essential for NRG1-ERBB signaling (glutamatergic circuit). | Failure in phagocytosis, glutamate uptake, neuronal maturation, myelination, and neurotransmission. | TNFα, IL-1α, and C1q induced iPSC-derived astrocytes (A1-like reactive state; C3+). | [71,72] |
| SERPINA3 | HY, 320; CTX, 293.8; MO, 196.3; MB, 183.1; TH, 176.3. | Inhibits the activity of proteases (cathepsin and chymases). | Regulates the expression of NF-κβ. Promotes macrophage migration and BBB dysfunction, as well as the formation of protein plaques. | TNF-induced iPSC-derived BBB co-culture model (inflammatory reactive state). | [73,74,75] |
| C1q | CTX, 135.3; WM, 131.6; MO, 126.7; P, 110.3; MB, 110.1. | Involved in inflammation and infection, ribosome biogenesis, protein synthesis, regulation of apoptosis, and transcription. | Implicated in excitatory and inhibitory synapse elimination. Causes activation of pro-inflammatory microglia. Prevents differentiation and maturation of oligodendrocytes. | Reactive astrocytes (GFAP+) in the P301S Tau transgenic mouse model. | [76,77] |
| C3 | MO, 143.3; WM, 121.9; P, 116.4; TH, 103.4; MB, 99.2. | Participates in the activation of the complement system. Chemoattractant for neutrophils. | Modulates microglial phagocytosis. Dysregulation of intraneuronal Ca2+ homeostasis and excitotoxicity. Disrupts dendritic morphology. | TNFα-induced knock-out IκBα transgenic mice astroglia (GFAP+). | [78,79] |
| GM-CSF | CTX, 0.1; HP: 0.1; AMY, 0.1; MO, 0.1; WM, 0.1. | Stimulates the growth and differentiation of hematopoietic precursor cells. | Induces proliferation of microglia and neuronal network dysfunction. Promotes the migration of inflammatory cells across the BBB. | Non-obese diabetic mice (model for secondary progressive multiple sclerosis) pro-inflammatory active astrocytes (GFAP+). | [80,81,82] |
| CXCL10 | P, 10.8; MO, 7.4; SC, 3.4; TH, 2.6; CTX, 2.6. | Chemotaxis, differentiation, and activation of peripheral immune cells, regulation of cell growth, and apoptosis. | Encourages immune cell infiltration and contributes to establishing a pro-inflammatory CNS environment. | Non-obese diabetic mice (model for secondary progressive multiple sclerosis) pro-inflammatory active astrocytes (GFAP+). Pro-inflammatory reactive astrocytes. |
[80,83,84] |
| CCL2 | TH, 43.4; MO, 32.7; CTX, 26.8; WM, 25.3; P, 21.9. | Chemotactic response and mobilization of intracellular calcium ions. | Controls the recruitment of perivascular leukocytes into the CNS and shifts to an inflammatory phenotype. Potentiates the activation of astrocytes and microglia, demyelination, and axonal loss. | EAE mouse spinal cord reactive astrocytes (GFAP+). TNFα-stimulated primary mouse astrocytes (GFAP+). |
[80,85,86,87] |
| IL-17 | WM, 79.8; BG, 79.7; SC, 79.6; MO, 79.1; AMY, 71.9. |
Involved in antimicrobial host defense and maintenance of tissue integrity. | Recruits NF-κβ activator 1 and subsequent pro-inflammatory cytokine production. Induces demyelination. | Angiostrongylus cantonensis mouse active A1 astrocytes (GFAP+, S100β+, C3+) | [80,88,89] |
| TrkB | HYP, 230; TH, 222.1; MB, 218.9; AMY, 201.9; CTX, 190.6. |
Regulation of neuronal survival, proliferation, migration, differentiation, and plasticity. | Promotes excessive NO production and neuronal dysfunction or death by inducing excitotoxicity. | EAE mouse spinal cord astrocytes (GFAP+) and human multiples sclerosis lesion astrocytes (GFAP+). Hippocampal astrocytes (GFAP+) in the lithium-pilocarpine temporal lobe epilepsy mouse model. |
[90,91] |
| NLRP3 | WM, 3.4; P, 2.1; MO: 2; SC, 1.9; TH, 1.6. | Mediates NLRP3 inflammasome activation. | Involved in neuroinflammation and mitochondrial dysfunction. | Hippocampal A1 astrocytes in the chronic intermittent hypoxia rat model (GFAP+, C3+, increased synaptic branches, junctions, end-point voxels, and decreased branch length). | [92,93,94] |
| ELOVL1 | WM, 165.7; MO, 152; P, 140.7; CTX, 116.9; BG, 115.6. | Participates in the LCFA elongation cycle. | Saturated LCFA mediates astrocyte-induced toxicity through lipoapoptosis (PERK pathway). | Neurotoxic reactive astrocytes in the TNF-α, IL-1α, and C1q-induced primary murine model. | [95] |
| FABP7 | CTX, 366.1; CB, 228.1; BG, 210.5; HP, 198.7; MO, 188. | Involved in fatty acid metabolism and establishing the radial glial fiber system in the developing brain. | Promotes the NF-κB-driven pro-inflammatory response, which is detrimental to motor neuron survival. | Spinal cord pro-inflammatory/neurotoxic astrocytes (GFAP+, FABP7+) in the hSOD1-linked ALS mouse model. | [96] |
| Notch 1 | BG, 16.1; WM, 14.0; TH, 13.9; MO, 13.5; MB, 12.3. | Regulates differentiation, proliferation, apoptosis, neurogenesis, gliogenesis, and neuritogenesis. | Promotes the secretion of pro-inflammatory neurotoxic factors, neuronal apoptosis, and axonal damage. | Contusive spinal cord injury rat neurotoxic A1 astrocytes (GFAP+, C3+, NICD+) and induced (TNFα, IL-1α, and C1q) primary astrocytes (A1 phenotype). | [97] |
| SRR | HYP, 13.4; CTX, 13.1; P, 12.7; TH, 12.5; CB, 12.5. |
Catalyzes the synthesis of D-serine, a key coagonist with glutamate at NMDA receptors. | May contribute to their neurotoxic effects by activating extra-synaptic NMDA receptors. | Primary mouse reactive astrocytes (GFAP+, C3+). | [98] |
| HMGB1 | CTX, 362.4; WM, 308.2; P, 286.2; HYP, 282.9; BG, 282.2. | It is a DNA chaperone involved in replication, transcription, chromatin remodeling, DNA repair, and genome stability. | Promotes the expression of pro-inflammatory cytokines through RAGE signaling. | Hippocampal astrocytes (GFAP+) and primary microglia-stressed A1 astrocytes in mice with sepsis-associated encephalopathy. | [99] |
| Kir 6.2 | CB, 12.4; CTX, 11.9; BG, 8.3; P, 8.2; MO, 8. | Subunit of ATP-sensitive potassium channels. | Mediates mitochondrial fragmentation, resulting in its malfunctioning. | Reactive A1 neurotoxic astrocytes (GFAP+, C3+) in an LPS-induced PD mouse model. | [100] |
| Lcn2 | CTX, 0.5; P, 0.3; MO, 0.3; BG, 0.1; TH, 0.1. | Iron-trafficking protein involved in apoptosis and innate immunity | Contributes to neuronal loss, pro-inflammatory cytokine expression, and immune cell infiltration | Pro-inflammatory astrocytes in LPS-induced primary spinal cord mice; TNFα, IL-1α, and C1q primary spinal cord A1 phenotype astrocytes. Contusive spinal cord injury rat astrocytes (GFAP+) |
[101,102] |
| Neurotrophic mediators | |||||
| FZD1 | MB, 6.2; CB, 5.8; HF, 4.7; TH, 3.4; HY, 2.9. | Involved in the Wnt/β-catenin signaling pathway, which is associated with neuroprotection. | An alteration of Wnt, a pathway controlled by FDZ1, contributes to Tau hyperphosphorylation, memory impairment, and increased Aβ production through GSK3 hyperactivity. Mediates midbrain dopaminergic neurodevelopment as well as its recovery after insults. |
MPTP-induced PD C57BL/6 mice activated astrocytes of the ventral midbrain (GFAP+) and primary astrocytes from mouse ventral midbrain and aNPCs from subventricular zone and midbrain co-culture (treated with MPTP and the Wnt inhibitor Dkk-1). | [103,104] |
| ARG1 | CB, 1.0; CTX, 0.5; MO: 0.4; P, 0.3; HP, 0.3. | Implicated in neuronal growth/regeneration and adaptive/innate immune responses. | The astrocytic urea cycle exerts opposing roles of beneficial Aβ detoxification and detrimental memory impairment in AD. | Aβ primary astrocyte cultures and reactive astrocytes from postmortem hippocampal samples of AD patients (GFAP+, ARG1+) and transcriptome data (KEGG pathway analysis). | [105] |
| Nrf2 | WM, 91.8; CTX, 86.7; P, 84.5; BG, 83.9; MO, 82. | Immune system maintenance. Upregulates genes that promote glutathione synthesis. Reduces the expression of pro-inflammatory cytokines. | Coordinates the upregulation of antioxidant defenses. Its deficiency promotes oxidative stress and abnormal neuroinflammation by the upregulation of pro-inflammatory cytokines and, therefore, neurodegeneration. | Familial ALS mouse models overexpressing Nrf2 astrocytes that induce neuroprotection (GFAP+, hPAP+) and primary astrocyte–motor neuron co-cultures. |
[106,107,108] |
| SPHK1 | TH, 8.5; P, 4.5; MB, 4.1; MO, 4.0; AMY, 4. | Regulates neuroinflammation response. Stimulates the activation of NF-kβ for IL-17 synthesis. Contributes to cellular survival. | Reduction of SphK1 expression can lead to defective microglial phagocytosis and dysfunction of inflammation resolution due to decreased secretion of specialized pro-resolving mediators. Sphk1 binds its receptor and facilitates GDNF-induced enhancement in the transcription of GAP43, a key protein in axons. | 6-OHDA hemiparkinsonian mouse (injected with desipramine for dopaminergic protection) protective A2 astrocytes (GFAP+, neuroprotective genes+). | [109,110] |
| MFGE8 | CTX, 61.8; CB, 56.4; MO, 55.9; P, 55.6; WM, 55.6. | Mediates angiogenesis and the anti-inflammatory response through phagocytosis and pro-inflammatory cytokine downregulation. | Promotes neural stem cell proliferation and migration toward ischemic brain tissues. Increases microglial phagocytosis of myelin debris and promotes remyelination. | MFGE8 overexpressing KO/BCAS mouse (AAV vector) astrocytes (GFAP+; CD45-/GLAST1+) and primary astrocyte-OPC neuron cultures | [111,112] |
| BDNF | HP, 8.2; CTX, 5.3; CB, 3.3; M, 3.3; P, 2.5. | Contributes to survival and differentiation of neuronal development, synaptic plasticity, and memory formation. | A decrease or polymorphism of BDNF is associated with cognitive decline, tau phosphorylation, synapse loss, and neurodegeneration. Promotes dendrite outgrowth and spine density | 5xFAD mice that overexpress BDNF reactive astrocytes (GFAP +). | [113,114] |
| TSP1 | TH, 14.3; CTX, 11.3; P, 10.8; MO, 10.8; MB, 4.4. | Involved in angiogenesis and promotion of cell adhesion. Contributes to neuroprotection against Aβ. | Regulates signaling pathways involved in inflammation. Determines peripheral Aβ homeostasis. | P301S Tau or C57 mouse-derived neuron–astrocyte co-cultures and neuron culture treated with ACM and anti-TSP1 antibody or recombinant mouse TSP1. | [115] |
| TGF-β1 | MO, 54.2, TH, 43.4, SC, 42, WM, 40, P, 39.2 | Plays an essential role in neuronal survival and modulates the expression and activation of other growth factors, like interferon-gamma and TNFα. | Any alteration in TGF-β1 signaling contributes to AD through reduced phosphorylation of Smad2/3 and downregulation of TGF-β1 type II receptor expression. | Reactive astrocytes (GFAP+) in SBE-LucRT mice to measure TGFβ signaling after stroke by occlusion of a distal middle cerebral artery. |
[116,117] |
Abbreviations: 6-OHDA: 6-hydroxydopamine; Aβ: amyloid beta; AAV: adeno-associated virus; ACM: astrocyte-conditioned medium; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; aNPCs: adult neural stem/precursor cells; ARG1: Arginase 1; ATP: adenosine triphosphate; BBB: blood–brain barrier; BCAS: bilateral carotid artery stenosis; BDNF: brain-derived neurotrophic factor; C1q: complement component 1q; C3: complement C3; CCL2: C-C motif chemokine ligand 2; CD49f: integrin subunit alpha 6; CNS: central nervous system; CXCL10: C-X-C motif chemokine ligand 10; Dkk-1: Dikkhopf-1; EAE: experimental autoimmune encephalomyelitis; ELOVL1: elongation of very-long-chain fatty acid protein 1; ERBB: EGF receptor family; FABP7: brain-type fatty acid-binding protein 7; FZD1: frizzled class receptor 1; GAP43: growth associated protein 43; GLAST1: glutamate aspartate transporter 1; GM-CSF: granulocyte–macrophage colony-stimulating factor 2; GSK3: glycogen synthase kinase 3; HMGB1: high-mobility group protein B1; hPAP: human placental alkaline phosphatase; hSOD1: human superoxide dismutase 1; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor alpha; IL-1α: interleukin 1 alpha; IL-17: interleukin 17; iPSC: human-induced pluripotent stem cell; KCNJ11 (kir6.2): ATP-sensitive inward rectifier potassium channel 11; KO: knock out; LCFA: long-chain fatty acid; Lcn2: Lipocalin 2; LPS: lipopolysaccharide; MFG E8: milk fat globule-epidermal growth factor 8; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-κβ: nuclear factor kappa-light-chain-enhancer of activated B cells; NICD: notch intracellular domain; NLRP3: nucleotide oligomerization domain (NOD)-like receptor protein 3; NMDA: N-methyl-D-aspartate; NO: nitric oxide; Notch 1: neurogenic locus notch homolog protein 1; Nrf2: nuclear factor erythroid 2-related factor 2; NRG1: Neuregulin-1; OPC: oligodendrocyte progenitor cell; PD: Parkinson’s disease; PERK: protein kinase R-like endoplasmic reticulum kinase; RAGE: receptor for advanced glycation end products; S100β: S100 calcium-binding protein B; SBE-lucRT: Smad-responsive luciferase promoter; SERPINA3: Alpha 1-antichymotrypsin; Smad: mothers against pentaplegic homolog; SPHK1: sphingosine kinase 1; SRR: serine racemase; TGF-β: transforming growth factor beta; TNFα: tumor necrosis factor alpha; TrkB: tyrosine receptor kinase B; TSP1: Thrombospondin 1; Wnt: wingless-related integration site. Brain regions: AMY: amygdala; BG: basal ganglia; CB: cerebellum; CTX: cerebral cortex; HP: hippocampus; HY: hypothalamus; MO: medulla oblongata; MB: midbrain; P: Pons; SC: spinal cord; TH: thalamus; WM: white matter. * Gene expression by brain region was obtained from the Human Protein Atlas (http://www.proteinatlas.org/, accessed on 13 May 2024). ** Data source: UniProt.org (accessed on 13 May 2024). *** Terminology used to describe astrocytes in the cited articles.