Blood–Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder

Abstract

Major depression represents a complex and prevalent psychological disease that is characterized by persistent depressed mood, impaired cognitive function and complicated pathophysiological and neuroendocrine alterations. Despite the multifactorial etiology of depression, one of the most recent factors to be identified as playing a critical role in the development of depression is blood–brain barrier (BBB) disruption. The occurrence of BBB integrity disruption contributes to the disturbance of brain homeostasis and leads to complications of neurological diseases, such as stroke, chronic neurodegenerative disorders, neuroinflammatory disorders. Recently, BBB associated tight junction disruption has been shown to implicate in the pathophysiology of depression and contribute to increased susceptibility to depression. However, the underlying mechanisms and importance of BBB damage in depression remains largely unknown. This review highlights how BBB disruption regulates the depression process and the possible molecular mechanisms involved in development of depression-induced BBB dysfunction. Moreover, insight on promising therapeutic targets for treatment of depression with associated BBB dysfunctions are also discussed.

Introduction

Worldwide, major depressive disorder (MDD) is a seriously public mental health problem with growing prevalence (Smith 2014; Kupfer et al. 2012). Depression is a common psychiatric disorder that severely limits psychosocial functioning and diminishes quality of life. Nearly one in five people experience depression during their lifetime (Malhi and Mann 2018; Slavich and Irwin 2014), and almost 75% of patients with MDD develop a recurrent depressive episode (Lythe et al. 2015; Yiend et al. 2009). In addition, psychiatric studies revealed that almost 60–70% of depression patients express suicidal tendencies at some stage in their lives and over 20% of cases ultimately pledge suicide (Yiend et al. 2009; Moller 2003). However, the current antidepressant treatments remain ineffective in a large subset of patients. It is estimated that only approximately 30–50% of depressed patients could benefit from currently available antidepressant interventions (Slavich and Irwin 2014; Hodes et al. 2015). Therefore, these features indicate that depression is associated with substantial social and economic burden. In fact, according to the World Health Organization, depression will be the first cause of disease-associated burden around the world by 2030 (Nobis et al. 2020; Malhi and Mann 2018; Friedrich 2017). Consequently, identifying more effective therapeutic targets for preventing and treating depression is urgently needed.

Depression is a complex and highly heterogeneous disorder. Despite advances in our understanding of the neurobiology of MDD, mechanisms associated with the pathogenesis of MDD are not well defined. It has been widely accepted that pathophysiology of MDD is multifactorial, as it involves the interaction among environmental and genetic factors (Pena et al. 2014). Mounting evidence has indicated that the development of depression is associated with chronic alterations in neural circuit structure and function (Nestler et al. 2002), dysregulation of hypothalamic–pituitary–adrenal (HPA) axis (Keller et al. 2017; Cheng et al. 2021; Menke et al. 2021), oxidant-antioxidant imbalance (Czarny et al. 2018; Greaney et al. 2019b), inflammatory and immunological processes (Najjar et al. 2013a; Sakrajda and Szczepankiewicz 2021; Beurel et al. 2020) and disruptions in the gut microbiome (Foster and McVey Neufeld 2013; Deng et al. 2021). Nevertheless, no single mechanism can satisfactorily explain all aspects of major depression. Notably, preclinical and clinical evidence suggests that dysfunction of blood–brain barrier (BBB) contributes to the pathogenesis of major depression (Kealy et al. 2020; Menard et al. 2017; Welcome 2020; Di Benedetto et al. 2016; Malik et al. 2020; Biala et al. 2013). As the interface of crosstalk among multiple central nervous system (CNS) cell types and blood-borne peripheral cells, increased cerebral microvascular permeability and disruption of BBB integrity may provide a parsimonious mechanism to explain the complex and variable presentation of major depression.

BBB is a dynamic and metabolic barrier that bi-directionally regulates the trafficking of ions, molecules, and cells between CNS and blood (Pulido et al. 2020). BBB separates the cerebral bloodstream from the brain parenchyma and functions to restrict the entrance of peripheral inflammatory cytokines, immune cells and neurotoxic factors into the brain parenchyma, thereby maintaining the homeostatic microenvironment of the CNS for proper neuronal function (Andreone et al. 2015; Bell et al. 2010; Alvarez et al. 2011).The functional BBB comprises brain endothelial cells sealed by tight junction proteins, pericytes, astrocyte endfeet and extracellular matrix (ECM) components (Bell et al. 2010; Chow and Gu 2015). Therefore, the barrier properties of BBB are regulated by these components and surrounding cells including neurons, microglia and even peripheral immune cells (such as neutrophils and macrophages) (Tran et al. 2016; Dudvarski Stankovic et al. 2016; Engelhardt and Ransohoff 2012).

It is widely acknowledged that disruption of BBB can precede or hasten the progression of various acute and chronic neurological diseases, including ischemic stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), epilepsy, and so on (Munji et al. 2019; Sun et al. 2020). In contrast to other major psychiatric disorders, MDD is critically involved in the development of disorders characterized by vascular endothelial dysfunction, such as cardiovascular disease and diabetes mellitus (Valkanova and Ebmeier 2013; Carney et al. 2002). Actually, major depression has been reported to be associated with an ~ 80% increased risk of cardiovascular morbidity and mortality (Seligman and Nemeroff 2015; Wood 2014). Moreover, it has been reported that neurovascular dysfunction with BBB hyperpermeability promotes depression (Menard et al. 2017). Additionally, the existence of MDD risk factors such as oxidative stress and neuroinflammation often exacerbates BBB disruption and complicates the pathogenesis of depression (Najjar et al. 2013b). To data, research on BBB dysfunction in depression has received much less theoretical attention than is warranted. Hence, more emphasis should be given to improved understanding of BBB-related pathogenesis in depression and developing potential therapeutic targets for protecting BBB integrity and improving depression symptoms.

In view of the increasing interest in BBB disruption contributions to depression pathogenesis, we review current knowledge on BBB dysfunction in depression, with an emphasis on recent advances elucidating underlying mechanisms. We also outline how BBB dysregulation is associated with MDD pathogenesis, providing a foundation for future research.

Involvement of BBB Dysfunction in MDD

Although the association of BBB breakdown and depression is controversial (Roszkowski and Bohacek 2016), evidence of an altered cerebrospinal fluid (CSF) to serum ratio of various molecules in depressed patients is suggestive of a compromised BBB integrity (Gudmundsson et al. 2007; Niklasson and Agren 1984). A cross-section study found that elderly depressed women had an elevated CSF concentration of amyloid beta as well as an increased the CSF/serum albumin ratio, indicating the increased permeability of the BBB and/or blood-CSF barrier (Gudmundsson et al. 2007, 2010). Additionally, as a neurotrophic factor produced by astrocytes, S100B can be detected in peripheral blood if the integrity of the BBB is disrupted (Derwall et al. 2009). Hence, S100B has been implicated in association with BBB damage and is used as a peripheral marker of the compromised BBB integrity (Loftis et al. 2018; Arora et al. 2019). Several clinical studies have reported that S100B levels were elevated in serum and CSF of patients with major depression (Arora et al. 2019; Rothermundt et al. 2001; Schroeter et al. 2002, 2013; Gulen et al. 2016).

Similarly, the involvement of BBB disruption in depression is supported by preclinical studies demonstrating that morphology of brain endothelial cells and tight junction proteins (claudin-5 and occludin) were altered after chronic stress exposure (Santha et al. 2015; Menard et al. 2017). A real-time in vivo two-photon microscopic imaging evidence showed that stress-susceptible mice exhibited a clear leakage of 40-kDa fluorescence-conjugated dextran into the perivascular area, which is suggestive of weakened BBB integrity following stress (Lee et al. 2018). Collectively, these studies demonstrate that the disruption of BBB plays a critical role in the development of depression.

Mechanisms Underlying Depression-Induced Disruption of the BBB

Alterations of Endothelial Tight Junction Proteins in Depression

Physiologically, the BBB endothelium is sealed by tight junction proteins (Sweeney et al. 2019; Zhao et al. 2015) and exhibits a low rate of transcytosis along with greatly restricted paracellular permeability (Lochhead et al. 2020; Butt et al. 1990). It is believed that tight junction proteins control the property of low paracellular permeability and contribute to establishing and maintaining physiological functioning of the BBB (Hashimoto and Campbell 2020). Hence, disruption of tight junctions might have contributed, to some extent, to the breakdown of BBB during major depression. The tight junctions are multiprotein complexes composed of transmembrane proteins, including different claudins, occludin, and junction adhesion molecules (JAMs), as well as the accessory cytoplasmic scaffolding proteins, zonula occludins (ZO-1, 2, and 3) (Nian et al. 2020; Zihni et al. 2016; Reinhold and Rittner 2017; Zeisel et al. 2019). The strongest evidence of altered BBB integrity under MDD conditions comes from observation of downregulation of tight junction proteins in animal models of depression. A previous study demonstrated that the expressions of claudin-5 and occludin were significantly reduced in the frontal cortex and hippocampus of adult rats with depression induced by restraint stress (Cheng et al. 2015; Santha et al. 2015). Additionally, studies have suggested that chronic stress downregulates claudin-5, ZO-1 and occludin expression in the nucleus accumbens (NAc), increasing blood–brain barrier (BBB) permeability of circulating proinflammatory mediators and promoting the establishment of depression-like behaviors (Xu et al. 2019; Menard et al. 2017). Notably, the expression of claudin-5 was found to be decreased in the NAc of depressed patients (Menard et al. 2017).

The mechanisms underlying stress susceptibility of reduction in tight junction proteins are largely uncharacterized but there is evidence of stress associated loss of claudin-5 that is owing to decreased permissive acetylation of histones at the claudin-5 promoter within stress-susceptible mice (Dudek et al. 2020). Claudin-5 permissive epigenetic modification is associated with the upregulation of circulating proinflammatory cytokines in depression, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) (Pearson-Leary et al. 2017; Hodes et al. 2015; Dantzer 2018). Importantly, TNF-α/NF-κB signaling leads to increased expression of epigenetic repressor histone deacetylase 1 (HDAC1) in NAc endothelial cells, which plays a causal role in depression-induced claudin-5 loss (Dudek et al. 2020).

It should be noted that posttranslational modification of tight junction proteins may influence BBB integrity by regulating the expression, interactions and trafficking of tight junction proteins (Reiche and Huber 2020). How tight junction protein modifications are affected by major depression remains uncertain. The effects of phosphorylation of tight junction proteins are widely believed to result in increased BBB permeability (Soma et al. 2004; Yamamoto et al. 2008; Tatum et al. 2007). In cultured brain endothelial cells, increased phosphorylation of occludin, claudin-5 and ZO-1 has been reported to response to either TNF-α or IL-6 treatment (Rochfort and Cummins 2015; Rochfort et al. 2015). Moreover, the phosphorylation of ZO-1 caused by treatment with TNF-α and IL-6 diminishes occludin/ZO-1 association (Rochfort and Cummins 2015). Accordingly, inflammatory mediators released during major depression may induce phosphorylation of tight junction proteins leading to BBB hyperpermeability.

Collectively, there are only a limited number of studies on tight junction proteins dysfunction in MDD. As regulating endothelial junctional proteins may be an appropriate strategy to prevent BBB disruption, further investigations are warranted.

Pathological Changes of Cerebrovascular Endothelial Cells in Depression

As the fundamental component of the cerebrovascular system, brain endothelial cells predominantly relate to BBB homeostasis and function. Consequently, dysfunction of brain endothelium possibly causes BBB damage, which further exacerbates depression progression. Indeed, increasing numbers of clinical studies have confirmed that microvascular dysfunction contributes to the onset and progression of depression and have proposed a link between impaired endothelial functions and major depression (Geraets et al. 2020; Luca and Luca 2019; van Agtmaal et al. 2017; Lopez-Vilchez et al. 2016; Greaney et al. 2019a).For instance, recent studies have found a significant association between higher levels of plasma markers of endothelial dysfunction (sICAM-1: soluble intercellular adhesion molecule-1, sVCAM-1: soluble vascular cell adhesion molecule-1, sE-selectin: soluble E-selectin and vWF: von Willebrand factor) and depressive disorder (van Agtmaal et al. 2017; Geraets et al. 2020; Tchalla et al. 2015; Muller 2019; Lopez-Vilchez et al. 2016). Furthermore, besides considering a reliable marker of endothelial damage, vWF is also believed to be a trait marker for MDD as it is consistently higher in depressive patients irrespective of antidepressant treatment (Bot et al. 2015; Vischer 2006).

The precise regulation of molecular transport across the BBB is largely manifested within the endothelial cells. Endothelial cells permit rapid free diffusion of oxygen, carbon dioxide and small molecules between blood circulatory system and CNS (Pardridge 2015; Daneman and Prat 2015). While the permeability of other macromolecules across the BBB is tightly limited without endothelial transport systems (Zhao et al. 2015; Daneman and Prat 2015). Therefore, the deficiency of endothelial transport properties may initiate early BBB disruption in depression. The cellular transport properties are regulated by four major endothelial transport systems, including active efflux, carrier-mediated transport (CMT), receptor-mediated transport (RMT) and major facilitators-mediated transport (Zhao et al. 2015). It is noteworthy that alteration of BBB endothelial transporters is documented in some depressed patients. For instance, the function of P-glycoprotein at the BBB is inhibited in the chronically stressed rats (de Klerk et al. 2010). P-glycoprotein, encoded by the gene ABCB1, is the major ATP-binding cassette (ABC) efflux transporter at the BBB that transports xenobiotics and endogenous metabolites of brain into blood (Miller 2015; Pulido et al. 2020; Kreisl et al. 2015). The decreased transport activity of P-glycoprotein may facilitate accumulation of neurotoxic substances in CNS. Moreover, the functional polymorphisms of ABCB1 are significantly associated with MDD susceptibility (Fujii et al. 2012; Santos et al. 2014; Uhr et al. 2008) and explain individual differences in antidepressant response (Bruckl and Uhr 2016; Breitenstein et al. 2016; Schatzberg et al. 2015).

The CMT systems at the BBB, comprising the solute carrier (SLC) transporter family, are dedicated to facilitating the transcellular transport of a wide array of substrates, including carbohydrates, amino acids, hormones, fatty acids, amines, and vitamins (Lin et al. 2015; Daneman and Prat 2015; Pardridge 2015). The brain is the most energy-consuming organ and requires a continuous supply of carbohydrates as a source of metabolic energy (Quenneville et al. 2020).The glucose transporter 1 (GLUT1) at the BBB, encoded by the SLC2A1 gene, has been demonstrated to be a predominant transmembrane protein responsible for glucose CNS uptake (Patching 2017; Bell et al. 1993; Dick et al. 1984). Moreover, evidence indicates that GLUT1 plays a critical role in maintaining BBB integrity, and that GLUT1 deficiency leads to early BBB breakdown (Zheng et al. 2010; Winkler et al. 2015). Of note, decreased expression of GLUT1 was observed in amygdala of depressed Sprague–Dawley rats induced by repeat restraint stress (Xu et al. 2019). Furthermore, DNA methylation of the core promoter regions of GLUT1 was significantly increased in depressed patients compared to healthy comparison subjects, suggesting that defective GLUT1 is associated with major depression (Kahl et al. 2016; Bird and Wolffe 1999). On the contrary, other study showed the expression of GLUT1 was evaluated in the frontal cortex and hippocampus of restraint stressed Wistar rats (Santha et al. 2015). This discrepancy may be attributed to different species, and the distinct functional involvement of different brain regions in response to stress. Either way, the disturbances in brain energy metabolism in MDD may be partly caused by abnormalities in GLUT1-dependent glucose uptake (Stapel et al. 2019).

As described above, degradations in tight junction proteins, altered transcytosis and even cytoskeletal rearrangement (Najjar et al. 2013b) occur in brain endothelial cells during depression contributing to stepwise BBB dysfunction. Bioinformatic analysis of the brain endothelial transcriptome in mice subjected to social defeat stress reveled that oxidative stress and inflammation trigger endothelium impairment and altered endothelial cell function (Lehmann et al. 2020). Taking into consideration the importance of oxidative stress and inflammation in pathogenesis of depression, oxidative stress- or neuroinflammation-related endothelial dysfunction may represent different pathways in the development of depressive disorder.

Altered Cerebrovascular Pericyte in Depression

Pericytes are perivascular mural cells that surround the abluminal surface of brain capillary endothelium (Armulik et al. 2011). Previous studies provide evidence that pericytes play a critical role in the development and the maintenance of the BBB (Armulik et al. 2010; Sweeney et al. 2016). Pericytes loss or dysfunction was significant associated with BBB disruption in neurological disorders such as stroke and Alzheimer's disease (Cheng et al. 2018a; Halliday et al. 2016; Dalkara et al. 2011). Interestingly, in a recent study, NG2⁺pericytes were reported to increase in the hippocampus of depressed rats induced by chronic unpredictable stress (CMS) (Treccani et al. 2020). Moreover, NG2⁺pericytes were also shown a slight elevation in hippocampal of MDD patients, albeit not significantly (Treccani et al. 2020). The increased number of pericytes in CMS-treated rats is likely implicated in neuroinflammatory processes. In vitro study, there is a significant increase in proliferation of cultured brain pericytes after exposure to proinflammatory cytokine IL-1β (Treccani et al. 2020). Moreover, in response to proinflammatory processes, pericytes become activated and produce numerous inflammatory mediators detrimental to BBB function (Rustenhoven et al. 2017). In addition, pericytes also secrete matrix metalloproteases to degrade extracellular matrix and tight junction, which enhances BBB permeability (Rempe et al. 2016; Takata et al. 2011; Rustenhoven et al. 2016).

Compromised Astrocyte Function in Depression

Astrocytes are the predominant glia cells in CNS, which have emerged as key players in health and neurologic diseases (Smith et al. 2020; Linnerbauer et al. 2020; Pekny et al. 2016). Emerging evidence suggest that individuals with depression have a reduction in astrocytes density in the hippocampus (Cobb et al. 2016) and postmortem prefrontal cortex (Rajkowska et al. 2013; Si et al. 2004; Miguel-Hidalgo et al. 2010). Considering that the specialized astrocytes endfeet cover almost entire surface of the cerebral capillaries and regulate BBB integrity (Cheslow and Alvarez 2016), it seems reasonable to believe that the decrease of astrocytes contributes to BBB disruption and worsen the course of depression. A brain water channel Aquaporin 4 (AQP4) is particularly expressed in astrocyte endfeet along the BBB and responsible for regulating water flux between blood and CNS (Chu et al. 2016; Nagelhus and Ottersen 2013). Recent studies have demonstrated that increase in permeability of BBB is correlated with decreased AQP4 expression (Kim et al. 2020; Gao et al. 2020; Di Benedetto et al. 2016). Consistent with this notion, loss of perivascular AQP4 localization was observed in depressive patients and critically involved in the etiopathology of vascular depression (Rajkowska et al. 2013; Gur et al. 2020; Westermair et al. 2018). Notably, AQP4 deficiency exacerbates depressive-like behaviors in a chronic corticosterone subcutaneous injection model of depression (Kong et al. 2014). Thus, the increased vulnerability of astrocytes during depression progression may exacerbate BBB dysfunction.

Quiescent astrocytes have wide-ranging functions helping to maintain CNS homeostasis (Saba et al. 2020). While in the context of neuroinflammation, astrocytes respond to inflammatory signals and can themselves promote inflammation by releasing proinflammatory cytokines (Wang et al. 2020; Peng et al. 2015; Linnerbauer et al. 2020). Several studies have demonstrated that astrocyte-mediated neuroinflammation is associated with the pathogenesis of major depression (Leng et al. 2018; Ghaemi et al. 2018). Moreover, increased expression of proinflammatory factors in astrocytes is implicated in promoting BBB leakiness (Horng et al. 2017; Vainchtein and Molofsky 2020). Hence, a proinflammatory phenotype in astrocytes is considered as an important player in depression-related BBB dysfunction. Moreover, astrocyte-derived VEGF induces the endothelial NO synthase-dependent downregulation of tight junction proteins in endothelial cells, which eventually disrupts tight junctions and BBB integrity (Argaw et al. 2012; Vila et al. 2019; Sofroniew 2015). In line with these findings, elevated VEGF expression in depression may participate in a signaling cascade that eventually results in increased BBB permeability (Ryan and McLoughlin 2018; Shi et al. 2020; Lee et al. 2018).

Activation of Microglia Cells in Depression

Microglia are the primary resident immune cells in the CNS and are best known as critical mediators of the neuroinflammatory response (Subhramanyam et al. 2019; Xiao et al. 2013). Microglia constantly patrol brain parenchyma that act as sentinels and sensitively respond to microenvironmental changes in the CNS (Xing et al. 2018; Tremblay et al. 2011). In response to pathological stimuli, resting microglia are polarized to a proinflammatory state (M1) or an anti-inflammatory state (M2) (Xu et al. 2020; Kroner et al. 2014). Emerging evidence suggests that polarization of microglia toward the M1 phenotype is associated with the pathogenesis of depression, postmortem examinations have shown increased the expression of M1 microglial markers in patients with depression compared to healthy control (Bayer et al. 1999; Zhang et al. 2018; Setiawan et al. 2018). Furthermore, promoting M2 polarization of microglia is able to ameliorate depressive-like behaviors in chronic unpredictable mild stress (CUMS)-treated rodents (Gu et al. 2020; Li et al. 2020a; Wohleb et al. 2018). The M1 microglia secretes inflammatory cytokines, such as IL-1β and TNF-α, to cause the injury of endothelial cells (Chen et al. 2019; Cherry et al. 2014; Dudvarski Stankovic et al. 2016), perhaps aggravating BBB disruption in MDD. Proinflammatory microglia also cause P-glycoprotein dysfunction in brain endothelial cells through NADPH oxidase activation, contributing to the accumulation of neurotoxic proteins in the CNS (Matsumoto et al. 2012). On the other hand, during sustained neuroinflammation caused by depression, activated microglia may phagocytose astrocytic endfeet and impair BBB function (Haruwaka et al. 2019).

Disorder of the Microbiota-Gut-Brain Axis in Depression

In the last decade, the gut microbiota has become an integral part of the human physiology, providing important functions to the host. The gut microbiota has been recognized as the most important micro-ecosystem that possesses a profound impact on host metabolism (Kenny et al. 2020; Agus et al. 2018; Martinez-Guryn et al. 2018), the immune system (Iliev and Cadwell 2021; Cabinian et al. 2018), CNS (Jameson et al. 2020; Kundu et al. 2019) and physiology with implications for gut and systemic health (Rastelli et al. 2019; Makki et al. 2018). Recently, increasing evidence shows that gut microbiota may affect brain activity through the microbiota-gut-brain axis under both physiological and pathological conditions (Diaz Heijtz et al. 2011; Margolis et al. 2021; Mayer et al. 2019). Alterations in the composition of gut microbial ecosystem are involved in the pathogenesis of a wide range of neurological conditions (Willyard 2021; Rutsch et al. 2020). Accumulating evidence demonstrates that the microbiota dysbiosis, defined as imbalances in the composition, diversity and function of the gut microbiota, is involved in the etiology of depression, highlighting the association between gut microbiota and depression (Kelly et al. 2016; Valles-Colomer et al. 2019; Schmidtner et al. 2019).Mice with an alteration in the diversity and richness of the gut microbiota display depression-related behaviors (Desbonnet et al. 2015), and depressed individuals have been found to possess different composition and diversity of gut microbiota (Jiang et al. 2015; Zheng et al. 2016). Moreover, depressive symptoms can be induced in rodents by transplanting fecal microbiota from patients with major depression (Kelly et al. 2016; Zheng et al. 2016). Notably, probiotics are supposed to modulate the diversity of the microbiome and their metabolites, could potentially alleviate depressive and anxiety symptoms (Messaoudi et al. 2011; Akkasheh et al. 2016). An accumulation of data from both clinical and preclinical studies has demonstrated beneficial effects of probiotics on depression treatment (Liu et al. 2020; Akkasheh et al. 2016; Pinto-Sanchez et al. 2017; Marotta et al. 2019).

Altered gut microbiota in depression has been associated with various inflammatory responses (Lee and Mazmanian 2010; Chinen and Rudensky 2012; Maes et al. 2013), may contribute to BBB hyperpermeability (Eshraghi et al. 2020). In fact, it has been demonstrated that the functional gut microbiome plays critical roles in maintaining the integrity of the BBB. The lack of gut microbiota in germ-free mice is associated with increased BBB permeability and altered expression of tight junction proteins (Braniste et al. 2014), implying a causal role for the microbiota in BBB dysfunction. Moreover, the disturbance of gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), have essential metabolic and signaling functions which can modulate BBB integrity and brain function (Parker et al. 2020; Reichardt et al. 2014). In depression, prolonged stress-induced dysbiosis of gut microbiota increases intestinal permeability and lead to the translocation of inflammatory mediators, bacteria, or bacterial-derived agents into the peripheral blood, which could in turn further exacerbate BBB disruption (Cerovic et al. 2019; Wang et al. 2019; Kumar and Forster 2017; Rahman et al. 2018). This suggests that the destruction of BBB in depression may be the trigger of dysbiosis of gut microbiota.

Abnormality of Peripheral Immune in Major Depression

Previous studies have demonstrated a crosstalk between peripheral immune systems and major depression, as disruption in peripheral immune systems appears to contribute to a vulnerability to depression (Miller and Raison 2016; Brunoni et al. 2020; Gibney and Drexhage 2013; Beurel et al. 2020). There has been growing evidence that MDD is associated with aberrant inflammatory cytokine production, as indicated by increased levels of proinflammatory cytokines including IL-6, TNF-α, IL-10, IL-13, IL-18, IL-12 in the blood of MDD patients (Beurel et al. 2020; Kohler et al. 2017). It has been speculated that upregulated proinflammatory cytokines may be due to the activation of immune cell in depression. For instance, elevations in IL-6 and TNF-α were associated with a possible activation of monocytes/macrophages. Furthermore, MDD patients have been shown to exhibit elevated levels of circulating Th1, Th2, Th17 cells (Chen et al. 2011; Schiweck et al. 2020; Myint et al. 2005). Abnormal activation of Th1 and Th17 cells leads to increased secretion of IFN-γ, IL-2, TNF-α, IL-1β, IL-17, IL-21, and IL-6, which triggers inflammation response in depression (Boniface et al. 2007; Kuwabara et al. 2017; Menegazzi et al. 2020). Interestingly, both IL-6 and TNF have been shown to increase the permeability of the BBB, and blocking IL-6 or TNF actions decreases stress-induced BBB opening (Cheng et al. 2018b; Menard et al. 2017).

Besides systemic inflammation, a few studies have found neutrophil-to-lymphocyte ratio (NLR) to be elevated in MDD patients (Demir et al. 2015; Euteneuer et al. 2017; Velasco et al. 2020). Increased neutrophils in depressed patients can contribute to BBB damage by secreting matrix metalloproteinases (MMPs) (Horsdal et al. 2017; D'Amico et al. 2021; Kushamae et al. 2020). MMP-9 can initiate degradation of ECM and intercellular junction proteins, leading to BBB disruption (Ludewig et al. 2013; Hung et al. 2008). Moreover, MMP-9 also facilitates additional leukocyte recruitment, which subsequently promotes inflammatory cells infiltration into CNS, eventually contributing to BBB breakdown and neuronal injury (Zhang et al. 2019). Neutrophils can also produce ROS, which is known to disrupt junctional proteins of the BBB endothelium, leading to increased permeability (Yin et al. 2020; Szuster-Ciesielska et al. 2008). Altogether, these findings suggest that the immunological and inflammatory changes during major depression may play an active role in BBB damage. Nevertheless, how lymphocytes modulate BBB permeability during major depression remains poorly investigated. The time course of peripheral immune infiltration into brain and their exact role in BBB disruption and injury progression require further investigation.

Dysregulation of HPA Axis in Depression

The HPA axis is one of the most principal components of neuroendocrine system, which is responsible for regulating biological response to stressful stimuli (Lightman et al. 2020; Herman and Cullinan 1997). The HPA axis comprises stimulatory signals and glucocorticoid receptor-mediated feedback inhibition loops involving the hypothalamus, pituitary, and adrenal glands, which are important for maintaining glucocorticoid homeostasis and for preserving the normal physiology in the body (Charmandari et al. 2004; Scherholz et al. 2019; de Kloet et al. 1999; De Kloet and Reul 1987; Russell et al. 2010). The activation of HPA axis is initiated by the release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of the hypothalamus after stressor exposure. CRH and AVP then stimulate the pituitary gland to secrete adrenocorticotropic hormone (ACTH) into the bloodstream, which in turn leads to the production of cortisol from the adrenal cortex (Stratakis and Chrousos 1995; van Bodegom et al. 2017; Refojo and Holsboer 2009). On the other hand, cortisol maintains its normal physiological levels by providing negative feedback to the hypothalamus and pituitary to decrease the release of CRH and ACTH (Kalsbeek et al. 2006; Scherholz et al. 2019). However, unfortunately, the sensitivity of this negative feedback loop is impaired in depression, thus resulting in hyperactivity of the HPA axis with increased cortisol levels (Murphy 1991). Elevated basal cortisol has been shown to constitute the predictive maker of the risk for depressive episodes (Goodyer et al. 2001; van Bodegom et al. 2017; Pochigaeva et al. 2017; Fischer et al. 2017).

Several previous studies have shown that the pathophysiological mechanism underlying BBB dysfunction in depression may be related to aberrant function of HPA axis. Clinical investigations have demonstrated that cortisol administration can mediate endothelial dysfunction in healthy subjects (Broadley et al. 2006; Whitworth et al. 2000), and the pharmacological inhibition of cortisol production by cortisol biosynthesis inhibitor metyrapone can ameliorate endothelial dysfunction in patients with treated recurrent major depression (Broadley et al. 2006). Recently, corticosterone was reported to impair structural integrity and barrier function of neurovascular unit in the model of diabetes-related depression (Liu et al. 2019, 2021). Moreover, the proliferation of brain endothelial cells was significantly inhibited in depressed rats induced by corticosterone (Ekstrand et al. 2008; Johnson et al. 2006; Zhao et al. 2008). Accordingly, considering the overactivity of HPA axis in depression, raised cortisol levels in depressed patients can cause endothelial dysfunction leading to BBB impairment and neurovascular unit disruption, thereby facilitating susceptibility to depression.

Remarkably, glucocorticoids have been demonstrated as a therapeutic intervention for improving barrier properties of BBB in a number of neurological disorders including multiple sclerosis and blast-induced traumatic brain injury (bTBI) (Salvador et al. 2014; Hue et al. 2015). Mechanistically, glucocorticoids, such as dexamethasone, hydrocortisone, and corticosterone, could stabilize BBB properties by inducing the expression of endothelial tight junction proteins, including ZO-1, occludin and claudin-5 (Hue et al. 2015; Romero et al. 2003; Sadowska et al. 2010; Kroll et al. 2009; Forster et al. 2007). In that case, it seems to constitute a contradictory phenomenon, because increased secretion and reactivity of cortisol in MDD patients is a potent risk factor for BBB disruption in depression. In fact, glucocorticoids mediate their biological effects via interactions with cytosolic glucocorticoid receptor (GR), which is subsequently activated. Once activated, glucocorticoid receptors are able to translocate into the nucleus and bind to glucocorticoid response elements (GREs) on DNA to positively or negatively modulate target gene expression (Beato 1989; Tasker and Herman 2011). Therefore, a dysfunction of the GR may directly result in reduced expression of glucocorticoids-stimulated genes. Furthermore, the candidate GRE was identified within the distal part of the occludin promoter, indicating transactivation of tight junction proteins induced by glucocorticoids is dependent on GR (Harke et al. 2008; Salvador et al. 2014). It is worth pointing out that abnormalities in expression and function of GR have been reported in patients or animal models with depression (Anacker et al. 2011; Pariante and Miller 2001; Chiba et al. 2012; Cai et al. 2005). Thus, impaired GR signaling in depression is considered an important contributor to BBB disruption. At this point, glucocorticoid is ineffective or even harmful to BBB integrity in MDD.

Impact of BBB Hyperpermeability on Major Depression Development

BBB maintains homeostasis of CNS via limiting entry of potentially neurotoxic plasma molecules, peripheral myeloid cells and pathogens into the brain (Zhao et al. 2015). Once the property of BBB is impaired, the peripheral components will extravasate into the brain parenchyma and compromise of normal neuronal function. Indeed, a clinical study described the disruption of BBB in MDD patients about 40 years ago (Niklasson and Agren 1984). Recently, researchers are starting to tease apart the contribution of compromised BBB in depression (Menard et al. 2017; Cheng et al. 2018b). Evidence indicates the downregulation of claudin-5 is sufficient to induce depression-like behaviors in mice (Menard et al. 2017). Both IL-6 and TNF-α are shown to increase the BBB permeability and maintain prolonged depressive-like behavior in mice (Menard et al. 2017; Cheng et al. 2018b). It is important to note that loosening of the BBB is associated with allowing the recruitment and infiltration of peripheral immune cells or proinflammatory cytokines to the brain parenchyma. Recent post-mortem studies reported that both T and B lymphocytes and monocytes accumulated in brain parenchyma of MDD patients (Schlaaff et al. 2020; Enache et al. 2019). In line with these findings, increased Inflammatory T helper 17 cells recruitment and infiltration in the hippocampus and prefrontal cortex are sufficient to promote susceptibility to depression-like behaviors in mice (Beurel et al. 2018, 2013). These infiltrated peripheral signals are able to exacerbate neuroinflammation by activating microglia and other CNS cells, which lead to onset and progression of MDD (Komine et al. 2018; Ali et al. 2020; Nerurkar et al. 2019; Slavich and Irwin 2014). In brief, a prolonged neuroinflammatory response promotes the disruption of the synthesis, reuptake, and release of neurotransmitters and result in neuronal dysfunction, impairing affective neurocircuit function, such as behavior and cognition (Beurel et al. 2020; O'Neil et al. 2018; Stephan et al. 2012; Haroon et al. 2012; Yang et al. 2020).

On the other hand, disrupted BBB can cause irreversible microvascular dysfunction, which may play an important mechanism in the initiation or worsening of cerebrovascular diseases (Hu and Manaenko 2020; Farrall and Wardlaw 2009). Cerebrovascular disease has been thought to predispose, precipitate, or perpetuate the development of vascular depression (Taylor et al. 2013; Sneed and Culang-Reinlieb 2011; Tonhajzerova et al. 2020; Aizenstein et al. 2016). Impaired BBB function in the neurovascular unit can lead to cerebral perfusion deficits, resulting in structural disruptions of the fiber tracts in the cerebral white matter, which are visualized as white matter hyperintensities (WMHs) on results of magnetic resonance imaging (Wong et al. 2019; van Agtmaal et al. 2017). Evidences showed that diffuse WMHs are one of the major factors that cause emotional and cognitive dysfunction and have negative effects on quality of life (Aizenstein et al. 2016; Wen et al. 2014). Furthermore, a multicenter longitudinal study showed that WMHs to be associated with the persistence of depressive symptoms in later life. Greater WMH is a critical risk factor that likely reflects the severity of depression and predicting future depression risk, which supports the vascular depression hypothesis (Park et al. 2015; Teodorczuk et al. 2007).

BBB disruption allows extravasation of erythrocytes into the brain parenchyma from the blood circulation, resulting in cerebral microhemorrhages development (Fisher 2014; Sumbria et al. 2016; Weinl et al. 2015). The presence of intracerebral hemorrhage can cause dopamine (DA) neuronal injury and decrease of DA levels in ventral tegmental area, which may contribute to the depression-like behavior (Yang et al. 2018; Tan et al. 2015). Moreover, it was found that cerebral microbleeds was related to post-stroke depression symptom severity (Tang et al. 2011). In another population-based study, cerebral microbleeds, especially in deep or infratentorial brain regions, were associated with depressive disorders in participants free of stroke (Direk et al. 2016). It is indicated that cerebral microbleeds may be a specific vascular pathology only seen in the most severe form of depression. Overall, association of BBB dysfunction and depression indicate impaired brain iron homeostasis, excessive neuroinflammatory response, and reduced synaptic plasticity, and monoaminergic signaling, all which may contribute to the pathogenesis and etiology of depression (Fig. 1).

Fig. 1.

BBB breakdown and dysfunction in major depression. BBB is critical for maintaining CNS homeostasis by preventing the transportation of toxic substances from the circulating blood into the brain parenchyma. During major depression, functional and morphological alterations in the BBB endothelium, loss and mis-localization of tight junction proteins and the decrease in coverage of astrocytes lead to disruption of BBB. The destruction of BBB can exacerbate the progression of depression through a variety of mechanisms. Impaired endothelial function and BBB breakdown lead to cerebral perfusion deficits, resulting in brain damage and emotional and cognitive abnormalities. Moreover, microbleeds are associated with the loss of cerebrovascular integrity and BBB breakdown. Infiltrated immune cells and activated glia cells can release a plethora of inflammatory mediators and ROS that elicit neuroinflammation and neuron damage. In addition, increased metalloproteinase (MMP) activity in depression degrades endothelial tight junction proteins and basement membrane enhancing BBB damage

Therapeutic Potential of Targeting the BBB Dysfunction in Major Depression

To data, although many antidepressant treatments are available, most depressed patients fail to achieve a clinically appreciable improvement. Novel therapeutic strategies that target BBB deficits have emerged with promising results to obtain antidepressant effects. Approaches that potentially qualify for therapeutic BBB repair have shown preclinical therapeutic efficacy in protecting against depression. Blocking BBB disruption by inducing global anti-inflammatory response is sufficient to exhibit antidepressant actions (Cheng et al. 2018b). In addition, administration of lithium prevents the development of depressive-like behavior in a rat CMS model by attenuating stress-induced hippocampal BBB disruption (Taler et al. 2021). Another novel agent, Fenretinide (Fen), as the synthetic retinoid 4-hydroxy (phenyl) retinamide, is able to alleviate LPS-induced depressive-like behavior and BBB dysfunction in mice by regulating oxidative stress and inflammatory response (Li et al. 2020b). Increased expression and release of growth/differentiation factor 15 (GDF15) can promote astrocyte remodeling and strengthen the tight junctions between endothelial cells. This consequently results in the reduction of BBB permeability, which is responsible for improvement in the symptoms of depression (Malik et al. 2020). Collectively, these findings suggest that pharmacological modulation of BBB function may be suitable as an effective antidepressant strategy.

In addition to pharmacological treatment, aerobic exercise is increasingly recognized as an effective intervention to improve depressive symptoms among adults with major depression (Greenwood and Fleshner 2008; Brush et al. 2020; Gartlehner et al. 2016). Moderate physical exercise is documented to increases hippocampal volume and white matter integrity in healthy older adults, which represents a viable and appealing strategy for preventing cognitive impairment and depression (Colcombe et al. 2006; Tu et al. 2014; Smiley-Oyen et al. 2008; Patten et al. 2013). Moreover, physical exercise is also reported to improve oxidative stress-related endothelial damage, and thus limiting the occurrence and progression of vascular depression and dementia (Luca and Luca 2019). In fact, regular physical exercise is known to induce widespread beneficial effects on multiple body systems, including the CNS, peripheral nervous system, immune system, musculoskeletal and cardiovascular systems (Wilson et al. 2016; Simpson et al. 2015; Motl and Pilutti 2012; El Hayek et al. 2019; Lenk et al. 2010; Isojarvi et al. 2010). Therefore, exercise training may be involved in regulating BBB permeability in major depression through a variety of molecular and cellular mechanisms. Depression process is accompanied by increased inflammatory molecules and oxidative stress inducing vascular damage, while physical exercise is demonstrated to reinforce antioxidative capacity, reduce oxidative stress and induce the production of anti-inflammatory cytokines (Roh and So 2017; Chupel et al. 2018; Pedersen 2019; Esposito et al. 2003; Gleeson et al. 2011; Pingitore et al. 2015), and it may be implicated in preventing and diminishing the BBB damage. Additionally, physical exercise has been repeatedly shown to reduce the expression of metalloproteinases (Guo et al. 2008; Nascimento Dda et al. 2015; Zhang et al. 2013) and to improve the endothelial function and BBB integrity. Moreover, physical exercise can maintain BBB integrity by preserving tight junctions. Evidence indicates that exercise can diminish methamphetamine-induced disruption and redistribution of tight junction proteins and thus protect against methamphetamine-induced disruption of the BBB integrity (Toborek et al. 2013). Similarly, in a mouse model of multiple sclerosis (MS), physical exercise can attenuate experimental autoimmune encephalomyelitis by reestablishing the expression of tight junction proteins occludin and claudin-4 in the CNS to modulate the BBB permeability (Souza et al. 2017). Regular physical training can be recommended as a component of prevention programs developed for patients to minimize the risk of the depression onset as well as well to complement treatment.

Taken together, therapeutic interventions targeting disturbances in BBB function might therefore be effective in reversing or preventing pathological process of major depression. Further study is still required to understand the mechanism of BBB disruption during depression to develop more efficient treatments.

Conclusions

It is increasingly evident that the role of BBB dysfunction during MDD has been proposed as a major contributor to depression pathogenesis. Mechanisms underlying BBB dysfunction in depression is involved in modification of tight junction integrity, increased proinflammatory cytokines/chemokines, impairment of endothelial cell and pericyte functions and activation of glial cells which facilitates the neuroinflammations. Disturbing BBB permeability causes the recruitment of peripheral immune cells into the brain, which exaggerates cerebral inflammation and neuronal damage. Despite BBB disruption is observed in depression patients, it is unclear how BBB function is altered during the progression of depression and how the alteration is correlated with depression pathologies. It seems that the relationship between BBB disruption and depression is bidirectional. Specifically, on the one hand, depression can alter blood vessel ultrastructure, promoting BBB leakiness and passage of peripheral signals into the brain. Moreover, the involvement of depression risk factors and comorbid conditions further complicate the pathogenesis of the functional and anatomical changes of BBB that can exacerbate BBB dysfunction. On the other hand, disruption in BBB integrity is involved in the occurrence and progression of depression and associated with prolonged depressive-like behavior. Restoration of BBB integrity is associated with decreased risk of depression and improved depression symptoms. Accordingly, further understanding of how BBB dysfunction is causatively or consequently related to the overall pathogenic cascades of depression will offer opportunity to develop the novel therapeutic approaches for the treatment of depression.

Author Contributions

S.W. performed the literature search and wrote the manuscript, Y.Y. and L.D. contributed to the conceptualization of the review.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 82001425).

Data Availability

Not applicable.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.