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Fig. 1 | Acta Neuropathologica Communications

Fig. 1

From: Roles of neuropathology-associated reactive astrocytes: a systematic review

Fig. 1

Mechanisms of neurotoxic A1-like (C3+) reactive astrocyte polarization. a Neuroinflammation and the presence of misfolded, cytotoxic, or pathological proteins activates microglia, inducing an M1 phenotype that secretes TNF-α, IL-1α, and C1q [66, 76]. This combination of inflammatory signals is the primary mechanism of inducing neurotoxic astrocyte reactivity. b Microglial activation in response to pathogenic proteins is associated with excessive Drp1-Fis1-binding-induced mitochondrial fission, and subsequent release of mitochondrial fragments, a process that may work in conjunction with TNF-α, IL-1α, and C1q signaling to efficiently induce neuroinflammatory phenotype polarization [52]. c Prolonged glucose starvation induces astrocyte polarization to a pro-inflammatory phenotype that specifically displays significant upregulation of unfolded protein response genes [62]. d Activated endothelial cells induce astrocytic upregulation of C3, the extracellular matrix remodeling protein Decorin, and phagocytic functions [122]. e AD-associated amyloid accumulation is associated with activation of the NF-κB pathway in astrocytes, which adopt a C3 + neurotoxic phenotype [70, 74]. f In a TMT-intoxication model of AD, an influx of Ca2+ enters astrocytes via voltage-gated ion channels, resulting in mitochondrial membrane depolarization, upregulation of ROS and NOS, and pro-inflammatory astrocyte-associated C3 expression [28]. g Astrocytes with ALS-associated loss of functional TDP-43 adopt a neuroinflammatory phenotype, a response that is correlated with a loss of oligodendrocytes and indirect motor neuron damage [100]. h Exposure to IL-18 processed by the activated microglial NLRP3 inflammasome induces a C3 + synaptotoxic astrocyte response [44]. i Prion-propagating PrPSc + astrocytes upregulate C3 but also undergo distinct transcriptional changes that are considered pan-reactive [38]. j Astrocytes exposed to the T. gondii excreted-secreted antigens (TgESAs) underwent polarization to a C3 + reactive phenotype via NF-κB pathway activation [51]

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