Microglia-astrocyte crosstalk following ischemic stroke

Abstract

Ischemic stroke, the most prevalent form of stroke, severely impacts human health due to its high incidence, disability, and mortality rates. The complex pathological response to ischemic stroke involves the interplay of various cells and tissues. Among these, astrocytes and microglia, as essential components of nervous system, play significant roles in the pathological processes of ischemic stroke. In addition to their individual functions, an increasing number of studies have revealed that the interaction between astrocytes and microglia is crucial following ischemic stroke. It integrates current research reports to examine and clarify the effects of interaction between the microglia and astrocytes on the nervous system after ischemic stroke, aiming to provide new insights and approaches for future academic research and disease treatment.

Keywords: Astrocyte; Crosstalk; Inflammation; Ischemic stroke; Microglia.

Fig. 1

The dynamic changes of astrocytes and microglia following ischemic stroke and their functional roles. In the context of ischemic stroke or LPS stimulation of glial cells, the period from 1 to 7 days is considered the acute phase, and after 7 days, it is considered the subacute phase. Under the stimulation of LPS or ischemic stroke, resting microglia transition to an activated state. M2-microglia begin to appear within 24 h and the number of microglia peaks 3 to 5 days into the inflammation. After one week, as the inflammation enters the subacute phase, the number of microglia starts to decline and gradually decreases. During this process, M2-microglia secrete CD206, Arg, CCL22, IL-10, TGF-β, VEGF, TNF-β and BDNF. Within 24 h after the occurrence of ischemic stroke, M1-microglia begin to appear and gradually increase. M1-microglia reach their peak number 14 days after the stroke and become the predominant glial cell type. Activated astrocytes secrete IL-1β, IL-6, iNOS, TNF-α, NF-κB and MCP-1. During the acute phase, astrocytes secrete GSH, ROS, glutamate, IL-6, TNF-α and LCN2. Astrocytes also secrete laminin, fibronectin and chondroitin, which contribute to the formation of glial scars. In the subacute phase, astrocytes secrete TSP, Shh and Ca²⁺. Note: Note: LPS: Lipopolysaccharides; VEGF: Vascular Endothelial Growth Factor; TNF: Tumor Necrosis Factor; BDNF: Brain Derived Neurotrophic Factor; MCP-1: Monocyte Chemotactic Protein-1; GSH: Glutathione; ROS: Reactive Oxygen Species; LCN2: Lipocalin-2; TSP: Thrombospondins; TSP: Thrombospondins; Shh: Sonic hedgehog

Fig. 2

The mechanisms of crosstalk between astrocytes and microglia including EVs and molecular. 1) Activated astrocytes release S100B, which acts on RAGE on microglia, prompting the release of TNF-α, IL-1β, CCL22, and COX-2 from microglia. 2) sPLA2-A on astrocytes produces LPC, which acts on the G2A and P2 × 7R receptors on the microglial membrane, promoting the release of MCP-1 and CCR-2 from microglia. 3) Activated astrocytes produce sANPEP, which can convert Ang III to Ang IV. Ang IV acts on AT1R on activated microglia and prompts the release of IL-1β. 4) M2-microglia release extracellular vesicles rich in miR-23a-5p, which inhibits TNF in astrocytes, thereby suppressing MMPs. Additionally, miR-23a-5p inhibits the NF-κB pathway in astrocytes. 5) Extracellular vesicles released by M2-microglia contain miR-124, which can inhibit the STAT3 and pSTAT3 pathways in astrocytes. 6) Extracellular vesicles derived from microglia can also inhibit the Notch1 and promote Sox-2 pathways in astrocytes. 7) Astrocytes secrete PAI-1 to bind to LRP1, LRP1 can activate JAK/STAT1 pathway. Note: S100B: S100 calcium-binding protein B; RAGE: Receptor for Advanced Glycation End Products; COX: Cyclooxygenase; LPC: Lysophosphatidylcholine; G2A: G protein-coupled receptor 132; P2 × 7R: P2X Purinoceptor 7; MCP: Monocyte Chemotactic Protein; CCR: C-C Chemokine Receptor; sANPEP: Soluble Aminopeptidase N; MMP3: Matrix Metalloproteinase 3; STAT: Signal Transducers and Activators of Transcription; PAI-1: Plasminogen activator Inhibitor Type 1; LRP1: Low Density Lipoprotein Receptor-Related Protein 1

Fig. 3

The mechanisms of crosstalk between microglia and astrocytes. 1) LPS activates microglia and produces PGE2 through the iNOS-NO pathway. PGE2 acts on the EP1 receptor, and the activation of the EP1 receptor causes the endoplasmic reticulum to release Ca²⁺, increasing intracellular Ca²⁺ levels. The increased Ca²⁺ then acts on the PanX1 channel, causing ATP to be released from microglia. ATP, in turn, acts on the P2Y1R, further increasing the Ca²⁺ concentration in microglia. 2) LPS can promote the release of TNF-β by astrocytes. TNF-β can inhibit the production of NO in microglia and suppress the P2Y1R. 3) LPS can promote the generation of IL-10 in microglia. IL-10 can act on astrocytes and promote the production of TGF-β. 4) Microglia secrete IL-1α, which acts on astrocytes, increasing the expression of AQP4 on their surface. 5) Microglia can release IL-1β, which inhibits astrocytes from taking up glutamate. IL-1β can also inhibit the Rho-Rock pathway in astrocytes. 6) ORM-2 released by astrocytes inhibits microglia activity and suppresses the release of TNF-α and IL-1β from microglia. Astrocytes promote the release of HO-1 in microglia. 7) Activated microglia secret IL-1α, TNF-α and C1q to induce astrocytes. Note: PGE2: Prostaglandin E 2; P2Y1: P2Y purinoceptor 1; AQP4: Aquaporin 4; ORM-2: Orosomucoid-2; HO-1: Heme Oxygenase-1 Note: PGE2: Prostaglandin E 2; P2Y1: P2Y purinoceptor 1; AQP4: Aquaporin 4; ORM-2: Orosomucoid-2; HO-1: Heme Oxygenase-1