Abstract
The study by Sadowska and colleagues, featured in this edition of Journal of Cerebral Blood Flow and Metabolism, provides compelling insight into a critical mechanism of signaling that links somatic and brain inflammatory pathways. Brain inflammation is often treated as an isolated event, but the work by Sadowska et al clearly demonstrate that interleukin 1β crosses the fetal blood brain barrier, and that the rate of transfer increases after cerebral ischemia. It is, perhaps, time to link blood-borne cytokine signaling with alterations in the course of fetal brain development, especially after transient fetal hypoxia.
What links somatic and brain inflammation in the fetus? And under what circumstances should we care? The study by Sadowska et al, 1 featured in this edition of the Journal of Cerebral Blood Flow and Metabolism, provides compelling insight into a critical mechanism of signaling that links somatic and brain inflammatory pathways. In this work, Sadowska et al report that interleukin (IL)-1β can cross from plasma across the blood–brain barrier (BBB) of the late-gestation fetal sheep (127 days gestation; spontaneous parturition normally occurs at 147 days of gestation in this species), and that the transfer rate across the BBB is increased after a transient ischemic episode, caused by bilateral carotid occlusion.
Often, it is tempting to think of brain inflammation as an isolated event, especially when it is the result of transient ischemia or asphyxia. For example, it is logical to identify the local inflammatory response to asphyxia and resuscitation within the brain. 2 However, common stressors in utero, including umbilical cord occlusion and transient maternal ventilatory hypoxia, can result in redistribution of cardiac output, which in turn can disturb peripheral organ systems and stimulate inflammatory pathways in those organs. For example, hypoxic–ischemic encephalopathy in human patient populations is associated with elevated circulating concentrations of IL-1β 3 and IL-16. 4 Even subclinical hypoxic, ischemic, or asphyxic events can potentially result in inflammation outside the BBB that can have negative consequences within the BBB.
Systems biology analysis of gene expression patterns in the late-gestation fetal brain predicts that the major consensus developmental pattern (among hypothalamus, cerebral cortex, hippocampus, and brainstem) is development of the hematopoietic stem cell lineage. 5 Although it is not known whether immune development progresses in isolation in the fetal brain, it is likely that there is communication with the somatic immune system. Communication across the BBB is also likely the explanation for the observation that the brain inflammation response to transient brain ischemia/reperfusion 6 is dwarfed by the scope of the brain inflammation response to transient ventilatory hypoxia (which exposes the entire fetus to oxygen deprivation). 7
Although investigators have long recognized that circulating cytokines are likely to cross the BBB and promote brain inflammation, 8 the present study by Sadowska et al provides the first evidence that IL-1β can transverse the BBB and that the rate of transfer can be increased after a transient ischemia/reperfusion episode. In light of the larger universe of knowledge and in contrast to our tendency to quantify local synthesis of inflammatory mediators within the fetal brain, is it time for us to ask the broader question of whether transient, subclinical, asphyxic, or hypoxic episodes result in blood-borne cytokine signaling that alters the course of fetal brain development?
DISCLOSURE/CONFLICT OF INTEREST
The author declares no conflict of interest.