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English⧼Colon⧽ F9: Overview of the main alterations occurring at the blood–brain barrier (BBB) and in the interplay between neurons and glial cells during severe hyperbilirubinemia (A) and associated infection (B). The BBB is composed by endothelial cells (orange) and their tight (TJ) and adherens junctions (AJ), astrocyte end-feet (light blue spots), perivascular microglia (greenish-brown), pericytes (light-green), and the basement membrane (yellow). Circulation of unconjugated bilirubin (UCB) in the blood (yellow bullets) is provided by its binding to human serum albumin, but when the UCB levels greatly increase, interaction of unbound (free) fraction of UCB (Bf) with the BBB is enhanced, as well as its passage into the brain (A), by passive or facilitated diffusion. Entrance will be also facilitated by the increased number of caveolae and caveolin-1 upregulation. Then, mainly after long-term exposure, UCB decreases zonula occludens-1 and β-catenin levels, and thus TJ strands and cell-to-cell contacts, favoring UCB passage across the BBB. Pericytes will be damaged and glutathione homeostasis disruption, together with increased nitric oxide synthase expression, nitrite production, and cytokine release will cause endothelial cell degeneration. In the brain parenchyma, elevated levels of UCB will surpass protective mechanisms (see Figure 1) and will cause neuron (pink) degeneration and release of pro-oxidant factors (orange bullets), microglia activation that will first phagocyte debris (pink bullets), and together with astrocytes (blue) reactivity will secrete pro-inflammatory mediators (greenish-brown bullets). In addition, decreased number of myelinating oligodendrocytes (solid-green) is also observed. (B) When sepsis is associated to hyperbilirubinemia, increased alterations at structural and functional levels are produced. Endothelial cell and astrocyte end-feet degeneration, modified basement membrane composition, tight junction, and transporter system impairment, vascular protein leakage, extensive extracellular edema, and activation of metalloproteinases are hallmarks of BBB impairment. Facilitated entrance of blood-borne harmful substances may accelerate neuron degeneration and activate microglia and reactive astrocytes leading to the release of cytokines further damaging neurons and detrimentally affecting vascular endothelium. Cross-talk between monocytes and endothelial cells in this inflammatory state leads to reciprocal activation of the two cell types, allowing the diapedesis of monocytes and lymphocytes. Leukocytes extravasation across the activated endothelium includes its arrest and adhesion, as well as alterations in their morphology and transmigration. Alterations in BBB dynamic properties may favor the presence of albumin carrying UCB (1) and increased passage of lymphocytes (2) into the brain parenchyma. In this condition, astrocytes become over-reactive, microglia will acquire inflammatory/senescent phenotypes and both neurons and oligodendrocytes will degenerate. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes, and the excessive production of pro-inflammatory mediators and pro-oxidant factors may add on the prevention and recovery of neurologic sequelae resulting from unconjugated hyperbilirubinemia.