Astrocyte-Derived Proinflammatory Cytokines Induce Hypomyelination in the Periventricular White Matter in the Hypoxic Neonatal Brain

Abstract

Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD), a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL) loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC+ OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM) and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC+ oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

“…Astrocytes contribute to repair of the brain after insult; however, evidence is accumulating that reactive astrocytes mediate the pathophysiology of perinatal brain injury, potentially via the release of pro-inflammatory cytokines or hyaluronan [41][42][43] . We did not observe astrogliosis within the late-onset FGR brains; however, we have previously shown altered astrocyte morphology, without altered density, in late-onset FGR animals examined at term with altered astrocytic end-feet attachment at blood vessels, leading to altered cerebrovascular function [44] .…”

Nitric oxide and cytokine production by glial cells exposed in vitro to neuropathogenic schistosome Trichobilharzia regenti

“…Since tissue inflammation correlating with presence of the parasite and axonal damage was observed in infected mice as early as seven dpi [17], we primarily focused on detection of proinflammatory cytokines and nitric oxide. These factors are known to be produced by activated astrocytes and microglia and may contribute to pathological processes [26–29]. …”

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

“…Recent evidence has shown that IL-1β decreases the proliferation and survival rates of neural precursor cells by activating IL-1β/IL-1R signaling and upregulating p53 and p53-mediated genes, which leads to cell cycle inhibition and Puma/Bax-mediated apoptosis in neural precursor cells (Guadagno et al , 2015). Moreover, increased IL-1β production by microglia and astrocytes is linked to upregulated expression of IL-1R on oligodendrocytes and increased apoptosis of oligodendrocytes in periventricular white matter of neonatal brain (Deng et al , 2014; Xie et al , 2016). Thus, IL-1β is detrimental to immature brain with neonatal HIE through inhibiting the proliferation and survival of brain cells, such as neurons and oligodendrocytes.…”