Reactive astrocyte COX2‐PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

Abstract

Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy. In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal hypoxic-ischemic encephalopathy cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with “A2” reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit “A2” reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop “A2” reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.

Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury

“…Overall the data in this study on neuropathological findings and neuroinflammatory events associated with neuroinflammation alone was similar to what we have published previously (Favrais et al, 2011;Krishnan et al, 2017;Schang et al, 2014;Shiow et al, 2017;Van Steenwinckel et al, 2018).…”

“…Use of P1-P5 mice to model the preterm infant brain is supported by comparative studies of brain growth and oligodendrocyte maturation (Back et al, 2001;Dean et al, 2011;Dobbing and Sands, 1979) and reviewed in (Semple et al, 2013). Full descriptions of the model including systemic and central inflammatory response and neuropathology are available within these references (Favrais et al, 2011;Krishnan et al, 2017;Schang et al, 2014;Shiow et al, 2017;Van Steenwinckel et al, 2018).…”

“…In the present study, we tested the myelin-inducing ability of GSK247246 in a mouse model of PWMI induced by neuroinflammation driven by systemic inflammation (Favrais et al, 2011;Krishnan et al, 2017;Shiow et al, 2017). This paradigm mimics the clinical events of clinically silent perinatal infection/inflammation that are common in preterm born infants with WMI (Wu et al, 2009).…”

Lipopolysaccharide‐induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo

“…At P3, brains were collected for cell dissociation and CD11B+ cell separation using a magnetic coupled antibody anti-CD11B (Miltenyi, MACS Technology) as previously described in detail (Krishnan et al, 2017;Schang et al, 2014;Shiow et al, 2017). Microglia are the predominant CD11B cell in this model of injury by more than 100-fold compared with populations of either macrophage or neurtrophil (Krishnan et al, 2017).…”

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

“…We further studied MG/Mφ activation using expression analysis of sixteen genes and six protein markers previously associated with polarized expression states (Chhor et al 2013, Miron et al 2013 at 5 time points. Gene expression analysis was performed in CD11B+ cells isolated by magnetically activated cell sorting (MACS, Miltenyi Biotec) from PBS-or IL-1β-exposed mice as per our previous studies (Chhor et al 2017, Krishnan et al 2017, Shiow et al 2017. Prior FACS analysis has demonstrated that the ratio of MG to other CD11B+ cells in this isolate is greater than 50 to 1 (Krishnan et al 2017).…”