Neuroimmune communication contributes to both baseline and adaptive physiological functions, as well as disease states. The vascular blood–brain barrier (BBB) and associated cells of the neurovascular unit (NVU) serve as an important interface for immune communication between the brain and periphery through the blood. Immune functions and interactions of the BBB and NVU in this context can be categorized into at least five neuroimmune axes, which include (1) immune modulation of BBB impermeability, (2) immune regulation of BBB transporters, secretions, and other functions, (3) BBB uptake and transport of immunoactive substances, (4) immune cell trafficking, and (5) BBB secretions of immunoactive substances. These axes may act separately or in concert to mediate various aspects of immune signaling at the BBB. Much of what we understand about immune axes has been from work conducted using in vitro BBB models, and recent advances in BBB and NVU modeling highlight the potential of these newer models for improving our understanding of how the brain and immune system communicate. In this review, we discuss how conventional in vitro models of the BBB have improved our understanding of the 5 neuroimmune axes. We further evaluate the existing literature on neuroimmune functions of novel in vitro BBB models, such as those derived from human induced pluripotent stem cells (iPSCs) and discuss their utility in evaluating aspects of neuroimmune communication.

Systemic inflammation has been implicated in the progression of Alzheimer’s disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16–18-month-old female Tg2576 (Tg) mice, which overproduce human Aβ and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aβ, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1β, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aβ pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aβ. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aβ pathology could contribute to poor outcomes following a systemic inflammatory insult.

Ozone (O₃) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O₃ also harms the brain; acute exposure to O₃ has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O₃ inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O₃ exposure. In this study, our goals were to characterize neurobehavioral endpoints of O₃ exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O₃ behavioral effects. We evaluated O₃-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O₃, but not 2 or 1 ppm O₃, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (Ido1) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O₃ and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O₃ doses (1–3 ppm), suggesting that behavioral responses to O₃ can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O₃-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O₃, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O₃ exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O₃, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.

Reproductive success relies on proper establishment and maintenance of biological sex. In many animals, including mammals, the primary gonad is initially ovary in character. We previously showed the RNA binding protein (RNAbp), Rbpms2, is required for ovary fate in zebrafish. Here, we identified Rbpms2 targets in oocytes (Rbpms2-bound oocyte RNAs; rboRNAs ). We identify Rbpms2 as a translational regulator of rboRNAs , which include testis factors and ribosome biogenesis factors. Further, genetic analyses indicate that Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway, specifically through the mTorc1-activating Gap activity towards Rags 2 (Gator2) component, Missing oocyte (Mios). Cumulatively, our findings indicate that early gonocytes are in a dual poised, bipotential state in which Rbpms2 acts as a binary fate-switch. Specifically, Rbpms2 represses testis factors and promotes oocyte factors to promote oocyte progression through an essential Gator2-mediated checkpoint, thereby integrating regulation of sexual differentiation factors and nutritional availability pathways in zebrafish oogenesis.