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Neuroendocrine and Neuroimmune Mechanisms Regulating the Blood-Brain Barrier

Summary and Keywords

The blood-brain barrier (BBB) is a dynamic structural interface between the brain and periphery that plays a critical function in maintaining cerebral homeostasis. Over the past two decades, technological advances have improved our understanding of the neuroimmune and neuroendocrine mechanisms that regulate a healthy BBB. The combination of biological sex, sex steroids, age, coupled with innate and adaptive immune components orchestrates the crosstalk between the BBB and the periphery. Likewise, the BBB also serves as a nexus within the hypothalamic-pituitary-adrenal (HPA) and gut-brain-microbiota axes. Compromised BBB integrity permits the entry of bioactive molecules, immune cells, microbes, and other components that migrate into the brain parenchyma and compromise neuronal function. A paramount understanding of the mechanisms that determine the bidirectional crosstalk between the BBB and immune and endocrine pathways has become increasingly important for implementation of therapeutic strategies to treat a number of neurological disorders that are significantly impacted by the BBB. Examples of these disorders include multiple sclerosis, Alzheimer’s disease, stroke, epilepsy, and traumatic brain injury.

Keywords: neuroendocrine, neuroimmune, blood-brain barrier, glucocorticoids, sex differences, testosterone, estrogen, hypothalamic-pituitary-adrenal, microbiome, cytokines


Over the past two decades, the scientific community has grown to recognize and to appreciate the importance of neuroimmune crosstalk via endocrine pathways in human health and disease. Prior to this period, communication between neuroscientists and immunologists was quite limited, and early published findings were viewed as biologically irrelevant or primarily conceptual (Erickson & Banks, 2018). Although the brain was thought to be an immune-privileged organ, it is well known that components of the central nervous system (CNS) detect and mitigate pathogenic challenges through the blood-brain barrier (BBB), cerebrospinal fluid (CSF), and several major histocompatibility complex (MHC) molecules (Carson, Doose, Melchior, Schmid, & Ploix, 2006; Kipnis, 2016). Recent preclinical and clinical studies also support the existence of mutual, bidirectional neuroimmune axes as lines of communication between the CNS, endocrine organs, and immune system, and the BBB plays a prominent role in each axis. Two of the axes wherein recent studies have revealed a prominent role for the BBB are the hypothalamic-pituitary-adrenal axis (HPA) and the gut-brain-microbiota axis (Acevedo-Rodriguez et al., 2018; Logsdon, Erickson, Rhea, Salameh, & Banks, 2018; Oyola & Handa, 2017). This article will explore the interactions between the neuroimmune and neuroendocrine systems and how these interactions influence the structure and function of the BBB in human health and disease.

BBB Physiology and Pathophysiology

BBB Physiology

The concept of the BBB arose from studies by Paul Ehrlich through observations that dyes injected intravenously in the periphery did not penetrate the brain (Ehrlich, 1885). Later studies by Reese and Karnovsky revealed that the inability of the dye to penetrate the brain from the periphery was due to the modifications of the CNS capillary components in the brain compared to other organs. These modifications include lack of fenestrations and the presence of tight junction (TJ) proteins between adjacent brain endothelial cells (Reese & Karnovsky, 1967). Subsequent studies revealed that the construct observed by Reese and Karnosky also included astrocyte end feet processes, pericytes that ensheath the basement membrane, and brain capillary endothelial cells; cooperation among these cell types is critically important for the regulation and the movement of most substances from the periphery into the brain parenchyma. This vascular interface is known as the BBB, and it is required for maintenance of precise cerebral homeostasis (Figure 1) (Abbott, Patabendige, Dolman, Yusof, & Begley, 2010; Banks, 2016). The concept of the neurovascular unit (NVU) emphasizes the continual crosstalk and interactions between the BBB, other resident CNS cells such as neurons, microglia, and oligodendrocytes, and peripheral immune cells. Thus, BBB-NVU interactions form a network in which all cells are under constant surveillance and adapt their behavior to accommodate both healthy and disease states (Banks, 2016). Readers are referred to several excellent reviews on the BBB and NVU (Abbott, 2013; Banks, 2016; Keaney & Campbell, 2015; Zhao, Nelson, Betsholtz, & Zlokovic, 2015).

Neuroendocrine and Neuroimmune Mechanisms Regulating the Blood-Brain Barrier

Figure 1. Key cellular components of the blood-brain barrier (BBB).

Figure 1 illustrates the relationships between cells that comprise the BBB. Neurons and microglia are also included as part of the neurovascular unit (NVU), a conceptual framework that describes the interactions with the BBB, resident brain cells, and peripheral immune cells.

Neuroimmune Mechanisms at the BBB

The infiltration of immune cells from the periphery into the brain is a central indication that other components of the BBB such as TJ proteins and cytoskeletal proteins may be dysfunctional. Loss of BBB integrity is well documented in neuropathologies like multiple sclerosis (MS), Alzheimer’s disease (AD), epilepsy, traumatic brain injury (TBI), and stroke (Sweeney, Zhao, Montagne, Nelson, & Zlokovic, 2019; Zielinska, Van Moortel, Opdenakker, De Bosscher, & Van den Steen, 2016). At the onset of inflammation, peripheral leukocytes migrate through the tightly regulated BBB and enter myriad CNS compartments, including, but not restricted to, the cerebrospinal fluid (CSF), choroid plexus (Hooper, Littman, & Macpherson, 2012), meninges, perivascular spaces, and eventually into the cerebral parenchyma (Ransohoff, Schafer, Vincent, Blachere, & Bar-Or, 2015). Migration of leukocytes across the BBB during inflammation is a multi-step process. These steps are (Takeshita & Ransohoff, 2012):

  1. 1. Rolling: consists of weak adhesions between BBB endothelial cell selectins and leukocytes (e.g., neutrophils, monocytes, macrophages)

  2. 2. Activation: G-coupled receptor activation on leukocytes via chemokines resulting in increased expression of adhesion molecules on their cell surfaces

  3. 3. Arrest: interactions between adhesion molecules on the BBB endothelial cells and adhesion molecules on leukocytes

  4. 4. Crawling: preferred site for transmigration is sought out by the leukocyte as it crawls along the BBB endothelial cells

  5. 5. Transmigration: crossing of the leukocytes in between adjacent BBB endothelial cells and into the brain parenchyma

Two distinct pathways of leukocyte transendothelial migration (TEM) have been described in the literature. Paracellular diapedesis involves the trafficking of leukocytes via adjacent endothelial cell junctions, while transcellular diapedesis occurs via the formation of pore-like structures in endothelial cells that fosters an active protrusion of leukocytes pseudopods into the endothelial cell body (Engelhardt & Ransohoff, 2012; Muller, 2011). Although paracellular diapedesis is a favored mechanism for leukocyte extravasation in periphery tissues, the complexity and intricacies of brain endothelial cells allow certain immune cell types to favor transcellular diapedesis over paracellular diapedesis (Engelhardt & Ransohoff, 2012). The extravasation of leukocytes across the BBB has been implicated in many neurological diseases such as MS, stroke, and life-threatening infections like sepsis (Kuperberg & Wadgaonkar, 2017; Takeshita & Ransohoff, 2012; Wilson, Weninger, & Hunter, 2010).

Numerous studies have shown reduced expression of TJ proteins (occludin and claudin-5) and the upregulation of metalloproteinases (MMPs) in human brain microvascular endothelial cells after treatment with the serum of MS patients (Goncalves, Ambrosio, & Fernandes, 2013; Minagar et al., 2003; Rochfort, Collins, Murphy, & Cummins, 2014; Shimizu et al., 2014). Furthermore, the reorganization of BBB actin cytoskeleton via proinflammatory cytokines in MS patients contributes to the decreased expression of TJ proteins (Alvarez, Cayrol, & Prat, 2011; Ortiz et al., 2014). Likewise, oxidative stress at the BBB during the ischemic and reperfusion phases in stroke may also induce BBB dysfunction. In vitro oxygen-glucose deprivation and in vivo middle cerebral artery occlusion (MCAO) experiments conducted by Liu et al. showed that TJ proteins are decreased and redistributed along with an associated increase in MMP-2 (Liu, Jin, Liu, & Liu, 2012). These findings demonstrate the importance of the BBB in cerebral homeostasis and highlight the changes that occur when BBB integrity is perturbed.

Neuroimmune and Neuroendocrine Regulation of the BBB

Historically, most preclinical studies in neurological disorder research have used male animals. In an effort to correct this discrepancy and close the knowledge gaps in our understanding of sex-specific outcomes in disease, recent National Institutes of Health (NIH) requirements have shifted to include both sexes in all experiments. Successful implementation of this mandate will provide valuable insights to explain the discrepancies between preclinical animal models and clinical trials and potentially lead to the development of targeted therapies for males and females. The following sections will highlight the influence of sex on immune cells and examine how sex steroids regulate the BBB in normal physiology and in pathological conditions.

Sex Differences: Sex Steroids and Sex Chromosomes

Sex differences refer to both gonadal sex differences (i.e., sex steroids) and biological sex differences (i.e., XX or XY chromosomal differences) (McCarthy, Arnold, Ball, Blaustein, & De Vries, 2012). Males and females possess the same immune system components; however, their immune systems respond quite differently to immune stimuli (Klein, 2012). Differences in sex steroid responses have been studied extensively among the peripheral immune responses that occur during pathogenic infections and autoimmune diseases. These studies clearly demonstrate that females have stronger innate and adaptive immune responses than males (Jaillon, Berthenet, & Garlanda, 2019; Jaillon et al., 2016; Klein, Hodgson, & Robinson, 2012; Robinson, Lorenzo, Jian, & Klein, 2011). The chromosomal composition of individual sexes (especially the X chromosome) may also influence immune responses (Roved, Westerdahl, & Hasselquist, 2017; Ruggieri, Anticoli, D’Ambrosio, Giordani, & Viora, 2016). These findings highlight the importance of considering the independent actions of sex steroids versus sex chromosomes.

The nomenclature used to describe sex steroids and their signaling pathways is complex, and we will attempt to simplify the terminology within this review. In general, the most common sex steroids (i.e., estrogens, progestogens, and androgens) are synthesized by reproductive organs. Owing to their lipophilic nature, these hormones are easily able to cross the BBB. Sex steroid receptors such as estrogen receptors (ERs), progesterone receptors (PRs), and androgen receptors (ARs) also exhibit promiscuous ligand-binding properties. Most sex steroids signal through nuclear hormone-dependent receptor mechanisms, wherein sex steroid ligands bind to intracellular receptors that translocate to the nucleus and bind to DNA as transcription factors. Alternatively, there are numerous other pathways through which sex steroids may bind to sex steroid receptors at the membrane to activate signaling pathways, which may or may not regulate transcription. Readers are referred to several excellent reviews on sex steroid signaling (Boese, Kim, Yin, Lee, & Hamblin, 2017; Garg, Ng, Baig, Driggers, & Segars, 2017; Hewitt & Korach, 2018).

Sex Differences in BBB Structure and Function

The BBB provides a physical separation of vascular and CNS compartments in the body. BBB transport proteins help to regulate the movement of nutrients into the CNS; hence, it is important to understand how physiologic sexual dimorphisms in BBB composition regulate cerebral homeostasis (Loscher & Potschka, 2005). One of the most important transporters is the multidrug resistant protein P-glycoprotein (Pgp) (Fromm, 2004). Pgp is highly expressed in brain endothelial cells and functions as an efflux pump that allows the passage of a limited range of compounds. Thus, Pgp is thought to be protective by preventing the accumulation of toxic substances in the brain (Loscher & Potschka, 2005; Schinkel, 1999). Pgp expression patterns also differ widely between males and females. A decrease in functional Pgp at the BBB is highest in young females compared to young males (van Assema et al., 2012). Another important endogenously expressed BBB drug transporter isoform is the organic anion-transporting polypeptide 1a4 (Oatp1a4) (Ronaldson & Davis, 2013). The expression of this Oatp1a4 protein has been showed by Brzica, Abdullahi, Reilly, and Ronaldson (2018) to be increased in females compared to male rats. Interestingly, the same study showed that castrated male rats exhibit increases in Oatp1a4 protein expression compared to non-castrated males. However, the expression of Oatp1a4 protein at the BBB did not differ between ovariectomized (OVX) females and non-OVX female rats. These findings indicate that androgens are a critical determinant of Oatp1a4 expression at the BBB.

Age also plays a critical role in sexually dimorphic characteristics of the BBB, particularly in females. Bake and Sohrabji (2004) showed that hippocampal BBB permeability is increased in OVX aged female (reproductive senescent) rats compared to OVX young females. This increase in BBB permeability was exacerbated when estradiol replacement was initiated in the OVX aged females compared to vehicle-treated OVX aged female controls; in contrast, the same treatment paradigm decreased BBB permeability in OVX young females compared to vehicle-treated OVX controls. Subsequent studies from the same group revealed increased hippocampal expression of immunoglobulin G (IgG) coupled with abnormal claudin-5 junctional localization in OVX aged female rats compared to OVX young females. The findings from these studies demonstrate that age and sex play important roles as determinants of BBB permeability, junctional protein localization, and transporter expression. Additional studies are needed to determine how sex steroids and sex chromosomes may affect specific components of the BBB under healthy conditions as well as in pathological states.

Effects of Sex Steroids on Immune Function and Dysfunction at the BBB


The primary estrogens produced in the ovary are 17β‎-estradiol and estrone. Estrone is the most abundant ovarian estrogen, while estradiol is the most potent ovarian estrogen. In the CNS, over two decades of research have shown that most estrogens mediate anti-inflammatory responses primarily through classical and nonclassical signaling mechanisms via estrogen receptor-α‎ (ERα‎), ERβ‎, and G protein-coupled receptor 30/G protein-coupled estrogen receptor 1 (GPR30/GPER1), a transmembrane receptor. These receptors are expressed on numerous brain cell types including neurons, astrocytes, microglia, and brain endothelial cells. Owing to their lipophilic nature, estrogens and other sex steroids can diffuse across the BBB. Binding of sex steroids to their cognate intracellular receptors can alter the brain’s immunological transcriptional machinery. Similarly, ERs are also expressed in several immune cells including monocytes, neutrophils, and dendritic cells (Roved et al., 2017). While a comprehensive discussion of the mechanisms through which estrogens modulate immune responses in the CNS is beyond the scope of this article, the reader is referred to several excellent reviews, as this remains a fruitful topic of investigation (Smith, Das, Butler, Ray, & Banik, 2011; Vegeto, Pollio, Ciana, & Maggi, 2000; Villa, Vegeto, Poletti, & Maggi, 2016). Estradiol has been shown to be protective at the BBB via several mechanisms. First, estradiol has been shown to reduce inducible nitric oxide synthase (iNOS) activity and directly regulate the cytokine and adhesion molecule expression by the vasculature and leukocytes, including claudin-5 (Burek, Steinberg, & Forster, 2014; Cignarella et al., 2009; Dietrich, 2004; Gameiro, Romao, & Castelo-Branco, 2010). Other studies have shown that estradiol is critical for maintaining the BBB via inhibition of MMP-2 and MMP-9 activation during cerebral ischemia (Al-Tarrah, Moiemen, & Lord, 2017). Estradiol also modulates the anti-inflammatory protein annexin A1 (ANXA1), which has a role in BBB permeability by regulating tight junction protein expression (Cristante et al., 2013; Davies, Omer, Morris, & Christian, 2007; Nadkarni & McArthur, 2013). In the face of inflammation, estradiol treatment was shown to protect the BBB by increasing ANXA1 expression and suppressing lymphocyte trafficking and ICAM-1 expression (Maggioli et al., 2016).

A number of in vivo and in vitro studies have demonstrated a direct anti-inflammatory role for estrogens in specific BBB cells such as endothelial cells, astrocytes, and pericytes (Acaz-Fonseca, Sanchez-Gonzalez, Azcoitia, Arevalo, & Garcia-Segura, 2014). Estradiol, acting through ERα‎, has been shown to preserve brain endothelial mitochondrial function and viability against ischemic insult (Guo et al., 2010; Humphreys, Ziegler, & Nardulli, 2014). Platelet-derived growth factor β‎ (PDGFβ‎) is required for pericyte proliferation and maintenance. Mice with low PDFGβ‎ expression exhibit many characteristics of BBB dysfunction. Female mice administered estradiol showed increased PDGFβ‎ gene expression, suggesting that estradiol-mediated upregulation of PDGFβ‎ promotes normal BBB function (Armulik et al., 2010; Lindblom et al., 2003). It is important to note that the neuroprotective effects of estrogen on the BBB are highly dependent on age, and this is well demonstrated by studies showing BBB dysfunction in reproductive senescent animals given estradiol replacement therapy (Bake & Sohrabji, 2004; Kuruca et al., 2017; Sohrabji, Bake, & Lewis, 2013).


Progesterone is the major progestogen produced by the ovaries (Pluchino et al., 2009). Animal models of TBI have provided extensive evidence for a protective effect of progesterone on immune responses and maintenance of BBB integrity (Deutsch et al., 2013). Progesterone administration after TBI has been shown to be neuroprotective by attenuating brain edema, expression of proinflammatory cytokines, and the recruitment of peripheral immune cells into the brain parenchyma (Chen et al., 2008; Cutler et al., 2007; Grossman, Goss, & Stein, 2004; Shahrokhi, Khaksari, Soltani, Mahmoodi, & Nakhaee, 2010; Si et al., 2014). The reduction in brain edema is thought to arise from progesterone-mediated upregulation of Pgp efflux transporters and the aquaporin 4 (AQP4) transporter at the third ventricle, while decreasing the expression of AQP4 at the site of the contusion and at the lateral ventricles (Cutler et al., 2007; Guo et al., 2006). Moreover, recent studies indicate that progesterone administration increases circulating endothelial progenitor cells that mature into brain microvascular endothelium and contribute to improved neurological function and BBB integrity after TBI. Progesterone administration has been shown to be neuroprotective at the BBB in ischemic stroke (Deutsch et al., 2013). Following stroke induction in animal models, progesterone increased the expression of TJ proteins while decreasing the expression of MMPs and proinflammatory cytokines linked to an increase in BBB dysfunction (Aggarwal, Medhi, Pathak, Dhawan, & Chakrabarti, 2008; Ishrat, Sayeed, Atif, Hua, & Stein, 2010; Jiang et al., 2009; Xu, Li, Li, & Li, 2010). As with estrogens, it must be emphasized that the timing of progesterone administration, age, sex, brain area, and steroid preparations are all important factors to consider when studying the effects of progesterone at the BBB (Littleton-Kearney, Klaus, & Hurn, 2005; Murphy, Littleton-Kearney, & Hurn, 2002; Murphy, Traystman, Hurn, & Duckles, 2000; Sohrabji, 2007).


Limited studies have evaluated the effects of androgens on BBB structure and function. Testosterone and other androgens such as dihydrotestosterone mediate their biological effects through binding to androgen receptors (Gao, Bohl, & Dalton, 2005). The effects of testosterone on endothelial cells of the BBB is largely equivocal, as studies have demonstrated either increased, decreased, or no effect of testosterone on leukocyte adhesion and peripheral immune cell trafficking into the parenchyma (Death et al., 2004; Norata, Tibolla, Seccomandi, Poletti, & Catapano, 2006; Roved et al., 2017). Chronic depletion of gonadal testosterone in male mice has been shown to upregulate proinflammatory cytokines, increase astrogliosis, and decrease the expression of TJ proteins. In the same study, testosterone replacement abrogated the inflammatory features associated with the BBB dysfunction (Atallah, Mhaouty-Kodja, & Grange-Messent, 2017). In contrast, other studies have shown that acute testosterone administration increased the stroke infarct volume compared to controls (Hawk, Zhang, Rajakumar, Day, & Simpkins, 1998). Since testosterone can be aromatized, it is difficult to decipher whether the effects of testosterone administration are due to testosterone or its metabolite, 17β‎-estradiol. Thus, dihydrotestosterone may be a better tool to dissect the effects of androgens since it cannot be aromatized (Krause, Duckles, & Pelligrino, 2006). Taken together, the paucity of research on androgens and the BBB highlights the need for further investigation.

Regulation of the BBB by the HPA Axis

The HPA Axis

The HPA axis collectively comprises the organs and secretions whose activation results in the release of corticosteroid hormones (CORT) from the adrenal glands. Physiological actions of CORT are primarily regulatory and are involved in the establishment and maintenance of homeostasis. At the cellular level, corticosteroids interact with two types of steroid hormone receptors: mineralocorticoid receptors (MR), which bind CORT and aldosterone (ALD), and glucocorticoid receptors (GR), which bind CORT (Arriza, Simerly, Swanson, & Evans, 1988; Hollenberg et al., 1985). MR has a 10-fold higher affinity for CORT than GR, resulting in high receptor occupation at normally low circulating levels of hormone (Funder, 2017). GR occupancy increases as a result of elevated levels of hormone during stress and fluctuating hormone levels, which are linked to circadian or ultradian rhythms (Kolbe, Dumbell, & Oster, 2015). This occupancy profile suggests that the majority of CORT-regulated effects are mediated through GR. CORT modulate a number of systems and processes such as immunity, inflammation, metabolism, and energy balance in a variety of cell types (Burford, Webster, & Cruz-Topete, 2017). Importantly, CORTs have been shown to regulate the stability of the BBB (Lucassen et al., 2015). In the brain, MR expression is restricted to the neurons of limbic brain regions including the hippocampus, lateral septum, amygdala, and prefrontal cortex (McEwen, Luine, Plapinger, & de Kloet, 1975). In contrast, GR expression is more ubiquitous among neural cell types, particularly in neurons and glial cells (Nicolaides, Galata, Kino, Chrousos, & Charmandari, 2010). This section will focus on the role of glucocorticoids at the BBB.

Glucocorticoid Regulation of the BBB

Glucocorticoids (GCs) are a class of CORT with strong anti-inflammatory properties (Zielinska et al., 2016). Experimental studies have shown an upregulation of TJ proteins, increased electrical resistance, and reduction in vascular permeability following treatment with synthetic GCs (Buse, Woo, Alexander, Reza, & Firestone, 1995; Forster et al., 2005; Singer, Stevenson, Woo, & Firestone, 1994). GC treatment in physiological and pathological conditions has been shown to reduce leukocyte infiltration, enhance transendothelial electrical resistance (TEER), and increase the expression of efflux transporters (Bauer, Hartz, Fricker, & Miller, 2004; Chan et al., 2013; Paul & Bolton, 1995). Administration of GC inhibits the translocation of brain endothelial proinflammatory transcription factors such as nuclear factor kappa B (NF-κ‎B) and reduces the binding of GATA and activator protein 1 (AP-1) to DNA elements (Simoncini et al., 2000). The summative effect of blocking NF-κ‎B translocation and other proinflammatory signals via GC treatment is a reduction in several inflammatory cytokines and chemokines (i.e., IL-6, CXCL8, CCL2), decreased immune cell trafficking across the BBB, increased MMP inhibitors (i.e., TIMP-1, TIMP-3), and downregulation of endothelial integrins (i.e., ICAM-1, VCAM-1, etc.) (Dufour et al., 1998; Gelati et al., 2000; Hartmann et al., 2009; Shi et al., 2014; Zakkar et al., 2011).

The TJ protein occludin is important to the electrical resistance of the junction and contributes to the formation of aqueous pores within the junction (McCarthy et al., 1996). Occludin transcription is positively regulated by glucocorticoid response elements (GREs) (Harke, Leers, Kietz, Drenckhahn, & Forster, 2008). Claudin is another TJ protein regulated by GCs. The claudin family consists of at least 24 conserved proteins, several of which play a role in maintenance of the BBB, including claudin-1, -3, -5, and -12 (Krause et al., 2008; Tsukita, Furuse, & Itoh, 2001; Wolburg & Lippoldt, 2002). The 5’ promoter region of claudin-5 has been shown to contain several putative GREs that confer increased claudin-5 transcription following GC treatment (Burek & Forster, 2009; Forster, Waschke, Burek, Leers, & Drenckhahn, 2006).

GCs also have direct effects on other BBB components. Glial fibrillary acidic protein (GFAP) expression by astrocytes is negatively regulated by GCs; however, the decrease in GFAP expression is delayed by several hours following treatment (Laping, Nichols, Day, Johnson, & Finch, 1994). GR expression on astrocytes was shown to mediate the transcriptional repression of GFAP on astrocytes (Unemura et al., 2012). Pericytes also express GRs. Studies by Katychev, Wang, Duffy, and Dore-Duffy (2003) showed that in vitro incubation of pericytes with GC induced the appearance of apoptotic cells. Nonetheless, this apoptotic appearance is mitigated when a GR antagonist is added. Conversely, reports from other studies suggest that GC treatment elevates transforming growth factor-β‎ (TGF-β‎), which in turn enhances pericyte coverage and the development of increased barrier integrity (Kroll et al., 2009; Vinukonda et al., 2010).

Neuroendocrine and Neuroimmune Mechanisms Regulating the Blood-Brain Barrier

Figure 2. The role of the BBB in the hypothalamic-pituitary-adrenal axis. (Modified from Zielinska et al., 2016.)

Figure 2 depicts signaling mechanisms at the BBB in the absence and presence of GC administration. GC administration decreases binding of the proinflammatory transcription factor NF-kB. GCs also decrease expression of endothelial cell adhesion molecules (ICAM-1, VCAM-1) required for immune cell adhesion and extravasation from the periphery into the brain parenchyma. GCs upregulate TJ proteins occludin and claudin, increase pericyte coverage, and increase expression of the metalloproteinase inhibitors TIMP-1 and TIMP-3. The collective effects of GCs on BBB function result in (1) enhanced BBB integrity, (2) diminished proinflammatory cytokines (or chemokines), and (3) suppressed activation and proliferation of astrocyte end feet.

The BBB: A Gateway Within the Gut-Brain-Microbiota Axis

The BBB acts as a nexus between the brain and the gut. Ischemic stroke, MS, mood disorders (anxiety and depression), and neurodegenerative disorders such as AD and Parkinson’s disease (PD) have all been linked to dysfunctional bidirectional communication within the gut-brain-microbiota axis (Cekanaviciute et al., 2017; Evans et al., 2017; Morgan et al., 2012; Sampson et al., 2016; Singh et al., 2016; Vogt et al., 2017). Furthermore, the gut microbiome also plays an important role in the development of tissue barriers, metabolism, and immunity in the CNS (Backhed, Ley, Sonnenburg, Peterson, & Gordon, 2005; Braniste et al., 2014; Hooper et al., 2012). For example, the importance of the gut microbiome in early development of the BBB was demonstrated by Braniste et al. (2014) in germ-free (GF) mice. This group showed that GF mice (i.e., mice that have had no exposure to microbes after birth and during adulthood) had increased BBB permeability and reduced expression of TJ proteins occludin and claudin-5 compared to specific pathogen-free (SPF) mice, i.e., mice reared in an environment free of monitored mouse pathogens. The authors also found that fecal transfer of bacteria that produce short-chain fatty acids (SCFAs) from SPF mice into GF mice decreased the permeability of the BBB (Braniste et al., 2014). These findings suggest that the products of the gut microbiome, which are primarily SCFAs, may generate numerous responses at the BBB. The SCFA propionate has also been shown to protect the BBB from oxidative stress via nuclear factor erythroid 2-related factor 2 (NRF2) signaling (Hoyles et al., 2018). Other studies have shown that bacterial muramyl peptides produced in the gut are found in the brain and have been shown to be important in promoting sleep (Krueger, Pappenheimer, & Karnovsky, 1982a, 1982b; Logsdon et al., 2018).

Neurodegenerative diseases are also associated with alterations in the gut microbiome. Beneficial effects of gut bacteria have been reported in several studies. Ma et al. (2018) showed that the administration of ketogenic diet in young healthy mice shifted the gut microbiota from proinflammatory, harmful bacteria taxa (i.e., Desulfovibrio and Turicibacter) to beneficial bacterial taxa (i.e., Akkermansia and Lactobacillus). Beyond alterations in the gut microbiota, these mice showed significant increases in cerebral blood flow (CBF) and Pgp transporters on the BBB that facilitated the clearance of beta-amyloid, the primary component of extracellular plaques in AD (Ma et al., 2018). Other studies have also shown a protective effect of the gut microbe Clostridium butyricum on decreasing BBB permeability via glucagon-like peptide-1 (GLP-1) in a model of TBI (Li et al., 2018). Although these previous studies demonstrate a beneficial effect of the gut microbiome on maintaining BBB integrity, other studies suggest that the gut microbiome may also have deleterious effects. A notable instance of the microbiome causing BBB dysfunction is in the context of sepsis, a life-threatening systemic inflammatory condition. Studies that address the role of the gut microbiome in preclinical models of sepsis have shown that shifts in the gut microbiome are associated with an impairment in BBB function, as evidenced by increased leukocyte infiltration, upregulation of adhesion molecules, degradation of TJ proteins, and increased expression of toll-like receptors (TLRs) on the brain endothelium (Andonegui et al., 2018; Della Giustina et al., 2017; Hofer et al., 2008; Logsdon et al., 2018; Wang, Hu, Yao, & Li, 2018). Taken together, these findings support an emerging important role for the gut-brain-microbiota axis in BBB integrity and cerebral homeostasis.


While the importance of the BBB in human health and disease is well established, there has been a growing appreciation for the contribution of the immune and endocrine systems to BBB function within the last decade. It is critically important that scientists evaluate both in vitro and in vivo findings on BBB function in the context of sex differences. Equally important are the individual contributions of resident CNS cells and their interactions with peripheral immune cells with the BBB-NVU. In addition, a major role has emerged for the BBB as a nexus in the HPA axis and the gut-brain-microbiota axis. Thus, a comprehensive understanding of the neuroendocrine and neuroimmune influences on the BBB is essential for understanding how the HPA and gut-brain microbiota axes contribute to human health and disease. It is imperative that future research on the role of the BBB in prevalent neurological disorders such as AD, PD, stroke and other cerebrovascular disorders, epilepsy, and MS consider the impact of the immune and endocrine systems on disease outcomes. By applying these principles across preclinical and clinical studies, the scientific community will obtain more translationally relevant results that will, ultimately, lead to better diagnostic and therapeutic tools to treat neurological disorders.

Further Reading

Banks, W. A. (2016). From blood-brain barrier to blood-brain interface: New opportunities for CNS drug delivery. Nature Reviews Drug Discovery, 15(4), 275–292.Find this resource:

Boese, A. C., Kim, S. C., Yin, K. J., Lee, J. P., & Hamblin, M. H. (2017). Sex differences in vascular physiology and pathophysiology: Estrogen and androgen signaling in health and disease. American Journal of Physiology—Heart and Circulatory Physiology, 313(3), H524–H545.Find this resource:

Hewitt, S. C., & Korach, K. S. (2018). Estrogen receptors: New directions in the new millennium. Endocrine Reviews, 39(5), 664–675.Find this resource:

Keaney, J., & Campbell, M. (2015). The dynamic blood-brain barrier. FEBS Journal, 282(21), 4067–4079.Find this resource:

Logsdon, A. F., Erickson, M. A., Rhea, E. M., Salameh, T. S., & Banks, W. A. (2018). Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Experimental Biology and Medicine (Maywood), 243(2), 159–165.Find this resource:

McCarthy, M. M., Arnold, A. P., Ball, G. F., Blaustein, J. D., & De Vries, G. J. (2012). Sex differences in the brain: The not so inconvenient truth. Journal of Neuroscience, 32(7), 2241–2247.Find this resource:

Oyola, M. G., & Handa, R. J. (2017). Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: Sex differences in regulation of stress responsivity. Stress, 20(5), 476–494.Find this resource:

Roved, J., Westerdahl, H., & Hasselquist, D. (2017). Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. Hormones and Behavior, 88, 95–105.Find this resource:

Villa, A., Vegeto, E., Poletti, A., & Maggi, A. (2016). Estrogens, neuroinflammation, and neurodegeneration. Endocrine Reviews, 37(4), 372–402.Find this resource:

Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015). Establishment and dysfunction of the blood-brain barrier. Cell, 163(5), 1064–1078.Find this resource:


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