Microglia and macrophage phenotypes in intracerebral haemorrhage injury: therapeutic opportunities

Abstract

The prognosis of intracerebral haemorrhage continues to be devastating despite much research into this condition. A prominent feature of intracerebral haemorrhage is neuroinflammation, particularly the excessive representation of pro-inflammatory CNS-intrinsic microglia and monocyte-derived macrophages that infiltrate from the circulation. The pro-inflammatory microglia/macrophages produce injury-enhancing factors, including inflammatory cytokines, matrix metalloproteinases and reactive oxygen species. Conversely, the regulatory microglia/macrophages with potential reparative and anti-inflammatory roles are outcompeted in the early stages after intracerebral haemorrhage, and their beneficial roles appear to be overwhelmed by pro-inflammatory microglia/macrophages. In this review, we describe the activation of microglia/macrophages following intracerebral haemorrhage in animal models and clinical subjects, and consider their multiple mechanisms of cellular injury after haemorrhage. We review strategies and medications aimed at suppressing the pro-inflammatory activities of microglia/macrophages, and those directed at elevating the regulatory properties of these myeloid cells after intracerebral haemorrhage. We consider the translational potential of these medications from preclinical models to clinical use after intracerebral haemorrhage injury, and suggest that several approaches still lack the experimental support necessary for use in humans. Nonetheless, the preclinical data support the use of deactivator or inhibitor of pro-inflammatory microglia/macrophages, whilst enhancing the regulatory phenotype, as part of the therapeutic approach to improve the prognosis of intracerebral haemorrhage.

Injectable Gelatin Hydrogel Suppresses Inflammation and Enhances Functional Recovery in a Mouse Model of Intracerebral Hemorrhage

“…As shown in Figures 7A-D, the expression of both IL-1β and TNF-α was decreased over time in two groups, and the ICH + Hydrogel group showed significantly lower of both two pro-inflammatory cytokines than that in the ICH + Vehicle group (P < 0.001), indicating that the hydrogel is capable of anti-inflammation in the ICH mouse model. In general, proinflammatory cytokines are thought to be produced mainly by activated M1 microglia/macrophages in the brain (Bai et al, 2020), Our results have shown that the hydrogel injection can inhibit the M1 phenotype, which might explain the decreased expression of the IL-1β and TNF-α .…”

“…For brain implantation, like other implants, the immune response which partly depending on the characteristics of the implants such as biocompatibility significantly influences the interaction between the hydrogel and the surrounding host tissues (Tsui et al, 2019;Wissing et al, 2019). As a key innate immune cell in the brain, microglia is the most important defense against exogenous threats, where activated microglia/macrophages develop into two subtypes: pro-inflammatory microglia (M1, classically activated) and anti-inflammatory microglia (M2, alternatively activated) (Xiong et al, 2016), the polarization of which plays a crucial role in promoting the recovery of brain injury and nerve (Bai et al, 2020). Nevertheless, how to modulate the immune response and neuroinflammation through the implanted biomaterials such as hydrogel remains a great challenge to date.…”

Protective Effect of miR-340-5p against Brain Injury after Intracerebral Hemorrhage by Targeting PDCD4

“…It is documented that microglia will secrete a large amount of proinflammatory cytokines when stimulated [26]. Previous studies have demonstrated that microglia can be activated by ICH which contributes to the secretion of proinflammatory cytokines during the occurrence of disease [27]. Recently, miR-340-5p was determined to be involved in the anti-inflammatory effects of dexmedetomidine in the nervous system, and overexpression of miR-340-5p enhanced the protective effect of dexmedetomidine in LPS-stimulated BV-2 cells [23].…”

Longitudinal monitoring of microglial/macrophage activation in ischemic rat brain using Iba-1-specific nanoparticle-enhanced magnetic resonance imaging

“…1,2 Neuroinflammation in ischemic brain results from the activation of microglia, the brain-resident macrophages, and from blood-borne macrophages that infiltrate from the circulation. [3][4][5] Microglia rapidly develop a pro-inflammatory phenotype in response to acute stroke injury; meanwhile, activation of microglia also present reparative and anti-inflammatory roles through a regulatory/ homeostatic phenotype, which facilitates recovery. 3,[6][7][8][9] Neuroinflammation accompanies these changes in the phenotypes of the microglia/macrophages after ischemic stroke, with one phenotype predominating over another in a time-dependent manner.…”

“…[3][4][5] Microglia rapidly develop a pro-inflammatory phenotype in response to acute stroke injury; meanwhile, activation of microglia also present reparative and anti-inflammatory roles through a regulatory/ homeostatic phenotype, which facilitates recovery. 3,[6][7][8][9] Neuroinflammation accompanies these changes in the phenotypes of the microglia/macrophages after ischemic stroke, with one phenotype predominating over another in a time-dependent manner. 7,10,11 Dynamic analysis by ourselves and others have demonstrated that the location of the active microglia/macrophages with respect to the infarct in ischemic brain at different stages is a critical feature of these immune phenotypes.…”