Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes

Abstract

Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.

Keywords: Astrocytes; Microglia; Neurodegenerative diseases; Neuroinflammation.

Fig. 1

Potential relationships between neurodegenerative diseases and glial cells. The release of aggregated pathogenic proteins such as amyloid-β, tau, α-synuclein, mSOD1, and TDP-43, into the extracellular space drives the changes of microglia and astrocytes into their pro-inflammatory phenotypes. The predominance of the pro-inflammatory phenotype of microglia results in the increase of pro-inflammatory factors and a decrease of the phagocytic effect. The pro-inflammatory-phenotype astrocytes release pro-inflammatory factors, which can dysregulate the synaptic function, the blood-brain barrier, metabolic function, glutamate, extracellular ions, and blood flow. Ultimately, this can lead to neurodegenerative disease progression. A dotted line with a question mark represents a possible relationship, with a lack of evidence for a direct association

Fig. 2

Proposed signals associated with microglia and astrocytes. The pro-inflammatory microglia are activated by IFNs and LPS via the activation of NFκB and STAT1, and then release IL-1β, IL-12, IL-23, SOC3, CXCLs, CCLs, NO, TNF-α, and IL-6. The neuroprotective microglia are promoted by IL-4, IL-13, IL-10, and TGF-β via the activation of STAT3 and STAT6. The M2 microglia enhance the neurotrophic factor (IGF-1), FIZZ1, CD206, Arg1, Ym1, Chi3l3, Fzd1, IL-13, IL-10, IL-4, and TGF-β. The activation of NFκB induces pro-inflammatory astrocytes. The pro-inflammatory astrocytes are affected by IL-1β, IFN-γ, LPS, TNF-α, and IL-6, and they produce IL-1α, C1q, GM-CSF, CXCLs, CCLS, TNF-α, IL-6, and NO. The activation of STAT3 induces neuroprotective astrocytes. The neuroprotective astrocytes interact with anti-inflammatory cytokines such as IL-13, IL-10, TGF-β, and IL-4; IL-4 and TGF-β coordinate to promote protective effects, and IL-4 suppresses TNF-α, IL-6, and NO. CCL: C-C-motif chemokine ligand; CXCL: C-X-C motif chemokine ligand; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN-γ: interferon γ; IL: interleukin; LPS: lipopolysaccharide; NFκB: nuclear factor κB; NO: nitric oxide; STAT: signal transducers and activators of transcription; TNFα: tumor necrosis factor α

Fig. 3

Schematic of microglial activation, astrocyte activation, and their relationship. The pro-inflammatory phenotypes are neurotoxic, while the neuroprotective phenotypes are neuroprotective. CHF 5074 polarizes microglia from the pro-inflammatory to the neuroprotective phenotype. Microglia can switch from the neuroprotective to the pro-inflammatory phenotype in the context of type 2 diabetes, obesity, and insulin resistance. Some candidates (dimethyl fumarate, fasudil, minocycline, and copaxone) can potentiate the neuroprotective polarity of microglia. The pro-inflammatory microglia secret IL-1α, IL-1β, TNF-α, and C1q, which can change astrocytes into the pro-inflammatory phenotype. The pro-inflammatory astrocytes secret CCL2, CX3CL1, CXCL10, GM-CSF, and IL-1, which in turn activate the pro-inflammatory microglia. The phenotype transition of astrocytes remains to be clarified. The dotted lines with question marks represent a possible relationship, with a lack of evidence for direct association. M: resting microglia; A: astrocytes. Other abbreviations as in Fig. 2