Developmental differences in microglia morphology and gene expression during normal brain development and in response to hypoxia-ischemia

Abstract

Background: Neuroinflammation plays an important role in ischemic brain injury and recovery, however the interplay between brain development and the neuroinflammatory response is poorly understood. We previously described age-dependent differences in the microglial response and the effect of microglial inhibition. Here we investigate whether age-dependent microglial responses may be related to pre-injury developmental differences in microglial phenotype.Methods: Measures of microglia morphology were quantified using semi-automated software analysis of immunostained sections from postnatal day 2 (P2), P9, P30 and P60 mice using IMARIS. Microglia were isolated from P2, P9, P30 and P60 mice, and expression of markers of classical and alternative microglial activation was assessed, as well as transforming growth factor beta (TGF-β) receptor, Serpine1, Mer Tyrosine Kinase (MerTK), and the suppressor of cytokine signaling (SOCS3). Hypoxia-ischemia (HI) was induced in P9 and P30 mice using unilateral carotid artery ligation and exposure to 10% oxygen for 50 minutes. Microglia morphology and microglial expression of genes in the TGF-β and MerTK pathways were determined in ipsilateral and contralateral hippocampus.Results: A progressive and significant increase in microglia branching morphology was seen in all brain regions from P2 to P30. No consistent classical or alternative activation profile was seen in isolated microglia. A clear transition to increased expression of TGF-β and its downstream *

High-Mobility Group Box 1 Contributes to Cerebral Cortex Injury in a Neonatal Hypoxic-Ischemic Rat Model by Regulating the Phenotypic Polarization of Microglia

“…In our study, HI insult resulted in an increased expression of Iba-1 and a change in microglial morphology from branch to ameba-like. These results indicated that cortical microglia were activated after HI, consistent with previous research (Harry, 2013;Cengiz et al, 2019). Microglia can be differentiated into different subtypes after activation.…”

“…Previous studies have shown that microglia are activated in the pathophysiology of HIBD (Ferrazzano et al, 2013;Cengiz et al, 2019), and HMGB1, a pro-inflammatory factor, is upregulated in these activated microglia. Therefore, we explored whether microglial activation was induced in the cerebral cortex after HI.…”

Distinct Residential and Infiltrated Macrophage Populations and Their Phagocytic Function in Mild and Severe Neonatal Hypoxic-Ischemic Brain Damage

“…MGs, the major innate immune cells in the brain, are CD11b positive (Li et al, 2017 ) and coexist with another CD11b-positive cell population, MDMs, in developing brain under physiological conditions (Ginhoux et al, 2010 ). Increasing evidence has revealed that the activation patterns of MGs in response to HI differ throughout development (Cengiz et al, 2019 ). However, CD11b + cells are traditionally regarded as MGs even though both MGs and MDMs express CD11b (Denker et al, 2007 ; Su et al, 2019 ; Nishihara et al, 2020 ).…”

White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

“…Those authors found that the subtypes of microglia involved in regulating immunity differed among individuals of different ages and across different brain regions. For example, the expression of genes involved in the signaling pathway downstream of TGF‐β in microglia was recently suggested to be age‐dependent, and signaling through the TGF‐β pathway was increased in P30 mice after H‐I injury compared to P9 mice (Cengiz et al., 2019). Furthermore, according to a study by Lai et al, microglia isolated from embryonic and neonatal brains produced pro‐inflammatory cytokines at higher levels than microglia from brains of other ages (Lai et al., 2013).…”