Microglial Mechanisms and Therapeutic Potential in Brain Injury Post-Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a particularly common public health problem with a high mortality and disability rate and no effective treatments to enhance clinical prognosis. The increased aging population, improved vascular prevention, and augmented use of antithrombotic agents have collectively contributed to the rise in ICH incidence over the past few decades. The exploration and understanding of mechanisms and intervention strategies has great practical significance for expanding treatments and improving prognosis of ICH. Microglia, as resident macrophages of central nervous system, are responsible for the first immune defense post-ICH. After ICH, M1 microglia is firstly activated by primary injury and thrombin; subsequently, reactive microglia can further amplify the immune response and exert secondary injury (eg, oxidative stress, neuronal damage, and brain edema). The pro-inflammatory phenotype transmits to M2 microglia within 7 days post-ICH, which plays a key role in erythrophagocytosis and limiting the inflammatory secondary injury. Microglial M2 polarization has significant implications for improving prognosis, this process can be mediated through crosstalk with other cells, metabolic changes, and microbiota interaction. Clarifying the effect, timing, and potential downstream effects of multiple mechanisms that synergistically trigger anti-inflammatory responses may be necessary for clinical translation. Analyses of such intricate interaction between microglia cells and brain injury/repair mechanisms will contribute to our understanding of the critical microglial responses to microenvironment and facilitating the discovery of appropriate intervention strategies. Here, we present a comprehensive overview of the latest evidences on microglial dynamics following ICH, their role in driving primary/secondary injury mechanisms as well as neurorepair/plasticity, and possible treatment strategies targeting microglia.

Keywords: brain injury; intracerebral hemorrhage; mechanisms; microglia; utilization strategies.

Figure 1

The mechanisms of intracerebral hemorrhage (ICH). Brain-damaged mechanisms following ICH can be roughly classified into the primary brain damage and secondary brain injury. The primary brain damage is primarily attributed to the hematoma formed mass effect. The secondary brain injury includes coagulation cascade, neuronal damage, inflammatory response, oxidative stress, blood-brain barrier (BBB) disruption, and brain edema.

Figure 2

The correlation between microglia activation and the secondary brain injury. The M2 polarization of microglia can accelerate hematoma clearance through specifically phagocytosing the erythrocyte, hemoglobin and heme through CD36, CD163 and LRP1, respectively. Activated microglia can mediated the secondary brain injury via phenotypic changes and the release of a series of pro-inflammatory and anti-inflammatory factors.

Figure 3

Microglial activation is associated with the metabolic reprogramming and gut microbiota dysbiosis. In neuroinflammatory condition, the main immune pathway of microglia can transform into aerobic glycolysis from oxidative glycolysis. The gut microbiota dysbiosis caused by microglial activation post-ICH can in turn affect the neuroinflammation and functional deficits of ICH.

Figure 4

The intervention strategies targeting the microglial phenotypic transform post-ICH.