Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity. When a diseased artery within the brain bursts, expansion and absorption of the resulting hematoma trigger a series of reactions that cause primary and secondary brain injury. Microglia are extremely important for removing the hematoma and clearing debris, but they are also a source of ongoing inflammation. This article discusses the role of microglial activation/polarization and related inflammatory mediators, such as Toll-like receptor 4, matrix metalloproteinases, high-mobility group protein box-1, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron, in secondary injury after ICH and highlights the potential targets for ICH treatment.

Keywords: Inflammatory mediators; Intracerebral hemorrhage; Microglia.

Figures

Fig. 1

After intracerebral hemorrhage (ICH), microglia can be activated/polarized to two phenotypes, M1 and M2. The M1 phenotype can produce proinflammatory mediators (interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α)), chemokines, redox molecules (NADPH oxidase (NOX), phagocyte oxidase (PHOX), inducible nitric oxide synthase (iNOS)), and heme oxygenase-1 (HO-1). These factors lead to neuroinflammation, iron accumulation, and reactive oxygen species (ROS) production and finally cause brain damage. The M2 microglia can produce anti-inflammatory mediators (IL-10, transforming growth factor beta (TGFβ)) and promote hematoma clearance through phagocytosis and promotion of angiogenesis. The Nrf2 signaling pathway may be involved in this process. Because they can be activated to either an M1 or M2 phenotype, microglia may have both proinflammatory and anti-inflammatory roles after ICH

Fig. 2

Deletion of Nrf2 increases leukocyte infiltration but does not affect microglial activation in mice subjected to intracerebral hemorrhage (ICH). a–d Infiltrating neutrophils (MPO-positive cells; scale bar 40 µm) and activated microglia (Iba1-positive cells; scale bar 20 µm) were apparent in or around the injury site in Nrf2−/− and wild-type (WT) mice 24 h post-ICH. e Quantification analysis indicated that Nrf2−/− mice had significantly more infiltrating neutrophils than did WT mice at 24 h post-ICH; the number of activated microglia around the injury site was similar in Nrf2−/− and WT mice (both n = 3/group, *p< 0.05) [113]

Fig. 3

Cellular localization of heme oxygenase-1 (HO-1) in normal mouse brain. a In normal mouse brain, HO-1 immunoreactivity was observed in vascular-like structures. b–d HO-1 immunoreactivity (in green) was colocalized with CD31-positive cells (in red, an endothelial marker). Scale bar 50 µm

Fig. 4

In the early stage of intracerebral hemorrhage (ICH), activated microglia express high levels of heme oxygenase-1 (HO-1). The elevated HO-1 may affect cell function, promote iron accumulation, and increase inflammation. These changes result in high reactive oxygen species (ROS) production and an increase in brain damage (blood–brain barrier (BBB) disruption, brain edema, white matter injury, cell death, and neurologic deficits). In the late stage of ICH, high HO-1 expression in microglia and vascular endothelial cells may contribute to hematoma absorption and angiogenesis, thereby promoting neurologic recovery