Microglial iron trafficking: new player in brain injury

Abstract

Neonatal brain injury is a significant reason of neurodevelopmental abnormalities and long-term neurological impairments. Hypoxic-ischemic encephalopathy and preterm brain injury, including intraventricular hemorrhage are the most common grounds of brain injury for full-term and preterm neonates. The prevalence of hypoxic ischemic encephalopathy varies globally, ranging from 1 to 3.5/1000 live births in high-resource countries and 26/1000 in low-resource countries. Preterm birth's global incidence is 15 million, a significant reason for infant mortality and morbidity, permanent neurologic problems, and the associated social and economic burden. The widespread neurodevelopmental effects of neonatal brain injury could have an unfavorable impact on a variety of aspects of cognitive, linguistic, behavioral, sensory, and motor functions. Brain injury occurs via various mechanisms, including energy deprivation, excitatory amino acids, mitochondrial dysfunction, reactive oxygen species, and inflammation giving rise to different forms of cell death. The contribution of microglial activity in neonatal brain injury has widely been underlined by focusing on cell death mechanisms since the neuronal death pathways during their development are distinct from those in the adult brain. Iron accumulation and lipid peroxidation cause a relatively novel type of regulated cell death called ferroptosis. Neonates generally have biochemical iron inequalities, and their antioxidant potential is highly restricted, implying that ferroptosis may be significant in pathologic conditions. Moreover, inhaled nitric oxide therapy in infants may lead to microglial inflammation via ferroptosis and neuronal injury in the developing brain. This review article aims to summarize the studies that investigated the association between neonatal brain injury and iron metabolism, with a particular emphasis on the microglial activity and its application to the inhibition of neonatal brain injury.

Keywords: Neonatal brain development; brain injury in neonates; ferroptosis; ipid peroxidation; iron metabolism; microglia.

Figure 1

Flow diagram outlining the clinical outcomes of microglial ferroptosis resulting from preterm brain injury and hypoxic ischemic encephalopathy.

Figure 2

Components of ferroptosis pathway are shown graphically. Cells that are engaged in iron-induced free radical production (left), as well as GSH/GPX4 dysregulation (in the middle), have been found to be implicated in this process. To induce ferroptosis, erastin or RAS-selective lethal 3 (RSL3) inhibits the amino acid antiporter in system Xc and GPX4, resulting in lower activity of GPX4. The active site of GPX4 contains selenocysteine. Selenium-tRNA maturation requires the production of Isopentenyl Pyrophosphate (IPP). The plasma membrane’s ferroptosis suppressor protein 1 (FSP1) contains oxidoreductase activity, which lowers coenzyme Q levels and minimizes L-OOH accumulation. Lipoxygenase requires iron as a cofactor, which is provided by HO-1, ferritinophagy, and the labile iron pool (LIP). TFR1: transferrin-1, IREB: Iron-responsive element-binding protein-1, ACSL4, acyl-CoA synthetase long-chain family member 4; GPX, glutathione peroxidase; GSH, glutathione; LOXs, lipoxygenases; LPCAT3, lysophosphatidylcholine acyltransferase 3; PL, phospholipids; PL-AA-OOH, lipid hydroperoxides; NCOA4: nuclear receptor coactivator 4, PUFA : polyunsaturated fatty acid, Nrf-2: nuclear factor erythroid 2–related factor 2, ATF4: Activated transcription factors-4, Se: Selenium, CoQ₁₀:Coenzyme Q₁₀, CoQ₁₀H_{2 :} Reduced coenzyme Q_10, NAD(P)H: nicotinamide adenine dinucleotide phosphate.

Figure 3

Flow diagram outlining the underlying mechanisms contributing to neonatal brain injury and potential prevention mechanisms. Graphical illustration of the main pathophysiological mechanisms underlying the development of brain injury in the neonates, namely hypoxia-ischemia-reperfusion, hypoxia-hyperoxia, inflammation, hemorrhagic insults, and PBIs. GSH depletion, glutathione S-transferase (GST) deformation, and reduced glutathione peroxidase (GPX) expression are observed in ferroptosis in neonatal brain injury. Iron accumulation potentiates inflammation, ROS, and NO associated with preterm and neonatal brain injury. Inflammation, excess iron (nontransferrin-bound iron), intracranial hemorrhage in preterm infants, and hypoxia in preterm and term infants induce cell death via oxidative stress and lipid peroxidation. Nitric oxide induces hypoxic ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism. Different compounds may also show positive results in preterm brain injury and hypoxic ischemic encephalopathy, acting by attenuating different components of ferroptosis. EPO: Erythropoietin, FER-1: Ferrostatin-1, Lip-1: liproxstatin-1, LOX: Lipoxygenases, ACSL4: Acyl-CoA synthetase long chain family member 4, NOS inhibitor: nitric oxide synthase inhibitor.