Pro- and Anti-Inflammatory Effects of Stress in the Brain: Mechanisms and Implications

Pro- and Anti-Inflammatory Effects of Stress in the Brain: Mechanisms and Implications

Some stress protocols show a pro-inflammatory response in the brain and other systems characterized by a complex release of several inflammatory mediators such as cytokines, transcription factors, prostanoids and free radicals.

Such response might contribute to cell damage during several neuropsychiatric diseases related with stress (post-traumatic stress disorder, major depressive disorder, anxiety disorders, and schizophrenia). In particular, data from the clinical arena associate an increase in proinflammatory mediators with major depression.

This review considers the current status of knowledge of stress-induced inflammation in the brain. Interestingly, anti-inflammatory pathways are also activated in response to stress, constituting a possible endogenous mechanism of defense against excessive inflammation. Both in brain and digestive tract, stress exposure switch on a compensatory anti-inflammatory mechanism, the synthesis of deoxyprostaglandins. Pharmacological stimulation of its nuclear receptor, the peroxisome proliferator activated receptor (PPAR) gamma, prevents stress-induced inflammatory and functional damage both in the brain and in the digestive tract. This dual response deserves further attention in order to understand pathophysiological changes and possible new therapeutic approaches of stress-related neuropsychopathologies.

1. Introduction

The physiologist Hans Selye first defined the physiological responses to stressors and adapted the term stress from physics and engineering to introduce it in the medical vocabulary. He was the first to use the terms stress and “stress response” in a medical context [1]. This response, consisting of a three-phase mechanism, is the result of an adaptation necessary to allow the overcoming of situations in which an organism has to “fight or flight” to survive (e.g. higher blood pressure, faster cardiac rhythm, suppression of the digestive processes, or re-direction of blood to muscles). Nowadays, the stress response is considered a characteristic set of physiological, affective, cognitive and behavioral changes that can have costs for well being whether or not successful adaptation is achieved.

Stress is a dual phenomenon, since while this fast and reversible response is essential for survival, it may cause adverse effects when secretion of the stress hormones are sustained [2]. In this way, the “stress hormones” production during stress response is very similar to the inflammatory process, generated in an organism when is invaded by certain micro-organisms or after trauma or tissue damage. Both responses are closely related and are preserved during evolution [3].

Neurobiology of stress

The stress response begins with nervous impulses from the cerebral cortical centers when they perceive certain environmental stimuli through the specific sensorial systems or recall certain stressful experiences (being these real or unreal). These stimuli propagate to the limbic system, and induce the release of corticotrophin release hormone (CRH) in the paraventricular nucleus (PVN) of the hippocampus. CRH is released to the venous system reaching corticotrope cells of the anterior pituitary gland [4] which, once stimulated, produce pro-opiomelanocortin (POMC), a precursor macropeptide that will be converted to the adrenocorticotropic hormone (ACTH), beta-endorphin and the melanocyte stimulatory hormone-alpha (MSH-alpha).

The released CRH stimulates the locus coeruleus neurons in the brainstem to release noradrenaline (NA) at the nerve terminals distributed throughout the central nervous system (CNS) [5]. Stress is also able to stimulate the sympathetic nervous system (SNS), particularly fibers that innervate the adrenal medulla, activating the chromaffin cells to produce adrenaline.
ACTH acts on both fasciculata and reticularis zones of the adrenal cortex to synthesize and secrete glucocorticoids (GCs) [6], which, along with the catecholamines released by the stimulation of the SNS are the main “stress hormones” (others are also considered, but with secondary importance, such as glucagon and growth hormone). These glucocorticoids inhibit the HPA axis activity, by negative feedback mechanisms, and by binding to their receptors in the pituitary gland, hypothalamus and medial prefrontal cortex [7,8], blocking the CRF secretion and therefore the release of ACTH in the pituitary gland.

2. Neuroinflammation

Although the main mediators of stress response, glucocorticoids, are universally considered as anti-inflammatory agents in the periphery, in the recent years this classic view has been challenged at a variety of levels, mainly in the CNS (reviewed in reference 9). Thus, in the brain, GCs are not uniformly anti-inflammatory, and can be even pro-inflammatory. It has been shown at the levels of cell extravasation and migration, inflammatory messenger levels, and at the transcription factor level [9]. In the CNS, prior exposure to GCs can result in a “priming” of the immune response to a subsequent inflammatory challenge (the inflammatory stimulus is higher than expected when exposure to GCs does not take place). For example, a model of chronic unpredictable stress (different stressor each day) in rats, increases levels of the inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) following infusion of LPS (lipopolysaccharide, an inflammatory compound found in the wall of Gram negative bacteria, responsible for sepsis in humans, used as inflammatory challenge) into the prefrontal cortex [10], as compared to LPS alone. Even more striking, unpredictable stress augments TNF-alpha, IL-1beta, and protein levels of one of the main oxidant enzymes, inducible nitric oxide synthase (iNOS) in the hippocampus and cortex when LPS is administered peripherally, an effect that is glucocorticoid receptor (GR)-mediated [11]. Similarly, stress levels of corticosterone exacerbate excitotoxin-induced increases in IL-1beta and TNF-alpha mRNA and protein levels both in vivo and in vitro [12,13].

Inflammation is a complex set of coordinated mechanisms governed by the interaction of multiple specific mediators (cytokines, prostaglandins, chemokines, etc) released by different types of immune cells. In spite of the presence of the brain-blood barrier (BBB), the brain responds to peripheral inflammatory stimuli mounting a local inflammatory response, called neuroinflammation, and generating HPA axis activation, and other acute phase responses including lethargy, somnolence, fever and anorexia, referred to collectively as “sickness behavior”, aimed to maintain the body’s homeostasis threatened by injury or infection [14].

The inflammatory process is a protective mechanism, conserved during evolution in all types of organisms. However, when it is excessive in intensity (over expression or over activity of its mediators) and time (inefficient resolution), it becomes harmful and can exacerbate numerous diseases. In spite of being the CNS an immune- and inflammatory privileged organ (mainly by the presence of BBB), there is extensive evidence that an excessive inflammation within the CNS contributes to many acute and chronic degenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD); and others [15]. In addition, an increasing body of evidence indicates its role in some psychiatric diseases such as depression, post-traumatic stress disorder and schizophrenia [16,17].

Some of the known mechanisms by which stress increases neuronal damage are:  1) energetic metabolism disruption by inhibition of glucose transport in neurons and glia and consequent depletion of ATP levels [18]; 2) increase of susceptibility to excitotoxicity by increase of extracellular excitatory neurotransmitter glutamate [19] and 3) oxidative/nitrosative mediators accumulation such as the free radical nitric oxide (NO), prostanoids, due to activation of enzymes responsible of their synthesis and proinflammatory transcription factor, the nuclear factor kappa B (NF−kappaB) [20]. Activation of NF−kappaB is one of the earliest events in the stress-inflammation response. It controls the transcription of many of the acute phase proteins and inflammatory genes (20). We demonstrated experimentally for the first time that stress activates NF-kappaB in the brain. This occurs very early after the beginning of stress [21], and later studies showed this activation in humans too, with psychological stress (free speech and a mental arithmetic task) [22].

NF−kappaB produces the expression of genes responsible for the accumulation of oxidative/nitrosative and inflammatory mediators that finally contribute to cell damage or generate reversible or, in chronic conditions, even irreversible cellular damage. This makes NF-kappaB a very interesting new target for a therapeutic approach. Two main sources of oxidative/nitrosative mediators and inflammatory damage after stress dependent of NF-kappaB are inducible NO synthase (iNOS), which produces NO and peroxynitrite, and cyclooxygenase-2 (COX-2), which produces prostanoids.

These two enzymatic mechanisms have been presented as main regulators of oxidative damage in the brain, after acute or chronic stress exposure. Both of them represent the “pathological face” of two finely regulated physiological processes: NO and prostanoid synthesis:

– Inducible NO synthase, iNOS, is an enzyme that has been implicated in citotoxicity phenomena in a variety of pathological process such as AD, PD, and Huntington´s disease [23,24] due to the amount of NO released when it gets activated. This gas is a very reactive molecule that can react with other oxidative species such as O-2 to generate peroxinitrite ONOO-, which is responsible for the membrane damage by lipid peroxidation attack. Exposure to stress induces an increase in expression and activity of this enzyme in various brain areas (e.g., cortex and hippocampus) [25].

– Cyclooxygenase 2 (COX-2) is an isoform of the enzyme cyclooxigenase that is responsible for the synthesis of prostanoids at high levels during pathological process with a clear inflammatory component [26]. COX-2 activation is not only toxic, due to release of certain toxic prostanoids (like PGE2 which in brain is able to induce the release of glutamate [27] and generate cellular death by apoptosis [28]), but because during this synthesis free radicals are generated contributing to oxidative/nitrosative damage [29].

Stress and proinflammatory cytokines

In addition to glucocorticoids or excitatory amino acids that are released during the first stages of stress exposure in the brain, there are also some inflammatory cytokines that are produced after stress exposure [30-37]. Cytokines are soluble bioactive mediators released by various cell types both at the periphery (macrophages and lymphocytes), and in the brain (astrocytes and microglia), which operate within a complex network and act either synergistically, or antagonistically, and that are generally associated with inflammation, immune activation and cell differentiation or death. These include interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), chemokines and growth factors [14].

The best studied ones in the pathophysiological basis of stress response are the proinflammatory cytokines TNF, IL 1 and 6. These cytokines are produced at inflammatory sites, and can stimulate their own secretion from the cells producing them. Interestingly, they can also activate the HPA axis, resulting in a positive feedback loop. One of the proposed mechanisms by which glucocorticoids help to prevent an over stimulation of the HPA axis is by inhibiting the production of these cytokines [38].

Tumor necrosis factor (TNF)

TNF is a group of cytokines that is comprised of two forms, namely α and β, which are derived from two different genes. Many studies have been focused on the α form, because its production is increased in the CNS after damage due to traumatic injury, ischemia, infections or diseases that involve brain degeneration, playing an important role in the adaptive response to these conditions. However, TNF-beta can also be produced in excess causing tissue damage [39].

TNF-alpha is released in its soluble form from its membrane bound precursor by a membrane-anchored zinc metalloproteinase TNF-alpha convertase (TACE). Like other cytokines, TNF-alpha exerts its effects by binding first to specific surface receptors on target cells. There are two types of TNF receptors: the p55 and the p75 also called TNFR-1 and TNFR-2 respectively [40]. TACE cleaves pro-TNF-alpha from the cell surface releasing the mature form from the cell membrane [41]. Studies by Western blot analysis have shown constitutive expression of TACE protein in microglial cells and some astrocytes in the rat brain [42-44]. The human brain also appears to express high levels of TACE in neurons, astrocytes and endothelial cells [45].

The activation of TACE/TNF-alpha has been shown as one of the early consequences of exposure to stress in the brain: with just 30 minutes of restrain stress, TACE enzymatic activity in brain cortex is increased [21]. As predicted, a larger release of TNF-alpha has been found in brain cortex samples obtained from stressed rats. Whereas the activity of TACE was increased after half an hour of immobilization, the levels of soluble TNF-alpha were raised one hour after the onset of stress [21]. The implication of TACE in this process was demonstrated by the reduction of the TNF-alpha levels in stressed animals treated with TACE inhibitors [46,47].

Interleukin 1beta (IL-1beta)

Interleukin-1 beta (IL-1beta) is a pro-inflammatory cytokine that has been identified as an important mediator of neurodegeneration induced in multiple neuroinflammatory conditions [48]. Following CNS damage, IL-1beta is rapidly released from activated microglia. The actions of IL-1beta in the CNS are diverse and include induction of growth factors, reduction of glutamate release, enhanced gamma-aminobutyric acid (GABA) effects, modulation of neuronal responses to N-methyl-D-aspartate (NMDA) and glycine, and increased activation of iNOS. Furthermore, as an early cytokine, it increases the production of other cytokines, such as IL-2, IL-6, and TNF-alpha, contributing to inflammation [49].

As mentioned above, the release of catecholamines in the stress response has been associated with the induction of stress-induced pro-inflammatory cytokines and beta-adrenoceptors are critical for tissue IL-1beta induction [50]. Thus, a well documented case of pro-inflammatory cytokines induced by stress is IL-1beta. Many studies show that exposure to certain acute stressors (immobilization, inescapable tailshock, escapable tailshock and footshock) can potently increase the expression of IL-1beta in the CNS, being the hypothalamus the principal site where such changes are observed [51-55]. This IL-1beta mediates some of the responses that occur during stress such as monoamine and glucocorticoid release, cognitive impairments and “depressive-like” behaviors [56,57].

Interleukin 6 (IL-6)

Interleukin 6 (IL-6) is a pleiotropic cytokine produced by immune and nonimmune cells. Increased production of IL-6 has been associated with disturbances of homeostasis, such as trauma, sepsis, or inflammatory diseases. In sepsis and local inflammation, IL-6 is considered to be a final common mediator in the cytokine cascade to hyperthermia [58-60]. Tissue injury, or immune inflammatory reactions as well as physical (e.g., infection, trauma) or psychological stress, these are known to cause increased production of IL-6. In the case of psychological stress (footshock and immobilization), plasma concentrations of IL-6 are increased [61-63], and also brain levels induced by previous release of IL-1beta [64].

Finally, it has been described that IL-6 acts as a neuromodulator that is able to down regulate anxiety [65]. However, these results need further studies, because a more recent study has proved that feeding, exploratory, anxiety- and depression-related behaviors are not altered in interleukin-6-deficient male mice [66]. Indeed, IL-6 (as a pro-inflammatory cytokine) shares many actions with IL-1beta and for example, inhibits cell death when administered intracerebrally to rodents that are exposed to ischemic or excitotoxic insults. And by contrast, mice that over-express IL-6 show marked neurodegeneration, which indicates that chronic IL-6 expression has neurotoxic effects [14].

Monocyte chemotactic protein (MCP-1/CCL2)

MCP-1 is a CC type of chemokine. Chemokines are small (8-14 kDa) peptides mainly known by the essential role they play in cell migration and intercellular communication. They are produced in various tissues, brain among them, and act through their interaction with G coupled receptors. Currently about 50 different chemokines and 20 chemokine receptors have been identified. They were initially described as inducible cytokines that facilitated the recruitment of certain leukocytes to the inflammation sites. However, we now know that they also regulate certain cell activities such as adhesion, apoptosis, proliferation, phagocytosis, angiogenesis or metastasis [67].

For MCP-1, besides its chemo-attracting action for inflammatory response-involved cells, recent investigations show other actions such as their ability to attract neuronal progenitors towards injured brain areas [68,69], or the regulation of blood brain barrier permeability [70]. This, in addition to discovering that MCP-1 [71] and its main receptor (CCR2) [72] are constitutively expressed in neurons in multiple brain areas, recent findings suggests that MCP-1 can act as a modulator of neuronal activity and neuroendocrine functions. Because of this, there has been an interest into the  study of the possible protective role this chemokine may have: this possibility is partially confirmed by various studies [73,74] showing that MCP-1 inhibition on subunit 1 of the NMDA (N-methyl-D-aspartate) receptor (NMDAR1), and its protective effect against neuronal apoptosis caused by glutamate. Therefore, it is possible that MCP-1 compensates the increase of glutamate produced in inflammatory processes (excitoxicity), such as Alzheimer’s disease by reducing NMDAR expression. This hypothesis is in part confirmed by the observed induction of MCP-1 caused by NMDA treatment in organotypic cortico-striatal cultures [75], and in rat brain [76].

After observing MCP-1 induction by NA in astrocytes, we decided to analyze if this chemokine is involved in the effects NA has on neurons. Therefore, based on Joan Berman’s group work, according to which MCP-1 protects mixed neurons/astrocytes cultures against HIV-tat and NMDA [74], we checked that the MCP-1 released by astrocytes protects primary neuronal cultures against excitotoxic injuries (NMDA, glutamate or ischemia), and that MCP-1 blockade reduces the neuroprotective potential of NA [77].

These data seem to prove a dual role for this chemokine: there are some articles showing that the suppression of MCP-1, and the subsequent reduction in the number of immune response-associated cells attracted by MCP-1 can reduce the damage produced by the release of toxic and/or pro-inflammatory agents [78,79]. However, although MCP-1 over expression can have negative consequences for the nearby cells, strategies aiming at elimination (or even at a large reduction of activity) of this chemokine do not reduce certain inflammatory processes. In fact, there are studies showing the lack of beneficial effects resulting from MCP-1, or its main receptor CCR2 suppression [80,81].

The activity of MCP-1 and other chemokines seems to be important since it allows for the right functioning of the immune defense. Our experience suggests that (as well as for many other agents involved in brain inflammatory processes) while an excessive/uncontrolled MCP-1 expression is not desirable, the proper modulation of its expression facilitates viability for the surrounding cells. Meaning that MCP-1 over-expression does not seem to protect against amyloid beta (Aβ) accumulation in transgenic mice (Tg2576), but it facilitates the accumulation of Aβ oligomers in microglia [82]. On the contrary, MCP-1 receptor (CCR2) elimination in the same type of mice, accelerates Aβ accumulation and causes their premature death [81].

In order to analyze if the physiological elevation of NA levels in brain alters MCP-1 expression, we exposed rats to a stressing stimulus, a process known to elevate NA concentration in brain [83]. But the mere exposure to the stress protocol used did not significantly modify MCP-1 concentration. However, when the synthesis of glucocorticoids was blocked with metyrapone, a large increase in the concentration of MCP-1 was detected [84].

Certain in vitro studies have described the ability of glucocorticoids to inhibit MCP-1 synthesis in cell types like fibroblasts [85] or microglia [86]. Accordingly, other in vivo studies described similar effects in hippocampus [87], or peritoneal cells [88]; this has also been used to explain the anti-inflammatory properties of these hormones. We were able to confirm the inhibitory effect of corticosterone on MCP-1 production in astrocytes. This is in agreement with the observed increase of brain MCP-1 after stress, caused by metyrapone, and suggests that glucocorticoids and noradrenaline have opposite effects on MCP-1 production during the stress response.

3. Compensatory Mechanisms: an Anti-Inflammatory Pathway

All organisms have complex defense mechanisms that allow them to adapt to and survive stress and, despite stress can trigger an inflammatory response, one anti-inflammatory mechanism that has received great interest in the literature during the last years is certain cyclopentenone prostaglandins derived from the differential activation of COX isoforms by different physio-pathological stimuli. This latter mechanism is beginning to be considered as a possible local endogenous regulator of the inflammatory response in neurodegenerative conditions and has received considerable attention from the neuroimmunology field.

The most thoroughly studied anti-inflammatory prostaglandin (PG) is the 15-deoxy-prostaglandin J2 (15d-PGJ2), a structural, non-enzymatic derivative from the PG D2. This PG is the proposed endogenous ligand for the gamma isoform of the subfamily of peroxisome proliferator-activated nuclear receptors, PPARgamma. These receptors have been thought to be directly involved in the regulation of the inflammatory response in several animal models of neuropathologies having a clear associated inflammatory component [89]. PPARgamma also possesses a great number of synthetic ligands such as the family of anti-diabetic drugs known as thiazolidinediones (TZDs), which include rosiglitazone, troglitazone, pioglitazone, ciglitazone and rivoglitazone [90].

PPARgamma and its ligands are master regulators of cerebral physiology and potential therapeutic targets for the treatment of several pathological conditions within the CNS. This promising anti-inflammatory pathway is also strongly related to stress exposure. We have demonstrated that both synthetic and natural PPARgamma ligands prevent the inflammatory and oxidative/nitrosative consequences of stress exposure in the CNS of rats subjected to immobilization stress [91,92]. The mechanisms by which these compounds prevent these effects include inhibition of stress (acute and chronic)-induced increase in iNOS activity, NF-kappaB blockade (by preventing stress-induced IκBa decrease) and inhibition of TNF-alpha release in stressed animals. Other research has indicated the capacity of the PPARgamma agonists (TZDs and 15d-PGJ2) to reduce the expression of the pro-inflammatory cytokine TNF-alpha and iNOS, gelatinase B (MMP-9) and COX-2 in LPS-stimulated macrophages in glial cells and neurons. These proteins contribute to the inflammatory damage observed in certain neurological diseases [15]. PPARgamma agonists may also activate antioxidant pathways such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [93].

The neuroprotection afforded by treatment with PPARgamma agonists is extended to prolonged restraint stress paradigms (7 or 14 consecutive days). In this way, treatment with PPARgamma agonists exerts direct protective action on the cerebral glucose and glutamate metabolism disrupted after stress exposure (regulating the expression of the neuronal glucose transporter GLUT-3 and the predominant glial glutamate transporter EAAT-2), mechanisms to add to its above-discussed anti-inflammatory/antioxidant effects, adding new therapeutic implications to the management of patients at risk of stressful events [94].

All of these findings clearly support the view that immobilization stress activates PPARgamma in the brain, and pharmacological manipulation of intrinsic pathways such as PPARgamma could provide protection in neuroinflammatory conditions. A question of further interest is the possibility that this pathway serves as a mediator of “central neurogenic neuroprotection” or “adaptive plasticity”, as proposed in the stressed brain. It has been recently demonstrated that this pathway is finely regulated in the brain by stress hormones, including catecholamines, glucocorticoids and excitatory amino acids [95].

The possible use of exogenously administered PGJ2 as a tool to maintain anti-inflammatory balance in this condition deserves special attention. In fact, expression of COX-2 can be up- or down-regulated in situations of neuroinflammation. In basal conditions (inactivated stage), physiological PGD2 metabolites such as PGJ2 closes a negative feedback loop on COX-2 expression, whereas in activated stages, such as stress, COX-2 is activated by enhanced levels of PGD2 metabolites, with production of its main product, PGE2. By administering supra-physiological doses of PGJ2, one could expect an inhibition in COX-2 expression and PGE2 production, as seen in different models [96]. Accordingly, exogenous administration of PGJ2 should exert a more powerful anti-inflammatory effect, as it occurs in the case of the antipyretic effect of this endogenous ligand. Thus, the anti-inflammatory effect of PGJ2 is more apparent in stressful situations than in resting status, due to induction of endogenous PGJ2 production, which, when combined with exogenous 15d-PGJ2, could exert a more powerful effect [96]. These observations support the rationale of using supra-physiological doses of PGJ2 as a possible therapeutic approach.

In addition, PPARs are constitutively expressed in vascular related cells and the treatment with their agonists could regulate the abnormal cerebral blood flow and glucose metabolism reported in individuals with psychiatric disease [97-99]. Its constitutive presence in endothelial and perivascular cells (a subset of brain-resident macrophages) suggest an important role regulating the infiltration of immune cells across the BBB, its permeability (regulation of expression and activity of matrix metalloproteases [100]), and the transduction of peripheral immune signals (as GCs, proinflammatory cytokines and prostaglandins) within the brain parenchyma to initiate a potentially deleterious neuroinflammatory process.

In a remarkable and novel mechanism, the TZD rosiglitazone might improve cognition by increasing dendritic spine density in discrete brain areas [101]. The precise mechanism might involve increased mitochondrial biogenesis or function, improving synaptogenesis and memory formation [101]. PPARgamma interactions with mitochondria are especially attractive because mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with neuropsychiatric diseases such as schizophrenia, bipolar disorder, and major depressive disorder, correlating increased psychiatric symptoms with declines in mitochondrial functional activity [102,103].

4. CNS-Immune System Relationship

In the last years clinical and experimental evidence has contributed to support the notion that psychosocial stress can activate the inflammatory response not only in the brain, but also in periphery. For example, peripheral blood mononuclear cells from healthy human volunteers subjected to stress (public speaking and mental arithmetic stressor) show significant increases in NF-kappaB activity. Furthermore, chronic stress in humans has been associated with increases in C-reactive protein (CRP), as well as IL-6 and other inflammatory mediators (reviewed in reference 104). Worth mentioning, it seems that the mechanisms of stress-induced activation of immune responses involve both sympathetic nervous system (SNS) and HPA axis pathways. Thus, as previously described (see point 2) glucocorticoids and neurotransmitters released in stress induce pro-inflammatory cytokines release (including IL-1beta, TNF-alpha and IL-6) and expression of their receptors. However, further investigation is required to fully understand the mechanisms involved in these effects.

Stress and innate immunity (Toll-like receptors)

Since description of the “General Adaptation Syndrome” by Selye it has been universally accepted that the stress exposure has consequences not only in the CNS but also in other regions of the organism (e.g. adrenal glands, immune organs, digestive system). As a consequence, the actions of stress on the immune system have been and are studied in depth, and in the last years the scientific research focus on the innate immunity and particularly on the neuroinflammatory actions of the Toll-like receptors (TLRs).

TLRs are key regulators and play essential roles in generating innate immune responses and specifically recognize the conserved microbial structural motifs referred as pathogen-associated molecular patterns (PAMPs) [105]. Ligand recognition by TLRs activates signaling cascades (including the activation of the transcription factor NF-kappaB and the activation of the MAP kinases p38 and JNK) that culminate in the transcription of many pro-inflammatory genes that encode cytokines, chemokines, and enzymes such as COX-2 or iNOS, which are events involved in the neuroinflammation detected after psychological stress exposure. Moreover, the presence of some TLRs (e.g. TLR2, TLR4) has been observed in microglia, astrocytes and neurons after inflammation in the CNS [106].

On the other hand, endogenous molecules released from disrupted cells and extracellular matrix degradation products also activate TLRs, and thus may contribute to immune activation (an inflammation) after tissue injury [107]. Interestingly, this activation by endogenous molecules can take place during the stress response: stress releases mediators that have been identified as ligands of TLRs such as heat shock proteins (e.g. HSP-60, which is an endogenous ligand of TLR4) [108].

There is evidence that psychological stress changes TLRs expression in the brain, (Gárate et al., personal communication), and there are data from other organs (such as in respiratory epithelial cells) indicating that is a plausible situation. Moreover it has been shown that TLR4-deficient mice after immobilization stress have a better behavioral condition compared with mice that express TLR4 normally, and that this effect is associated with a decreased inflammatory response (COX-2 and iNOS expression), and lipid peroxidation in brain tissue [109]. Similarly, another study has found that TLR4-deficient mice are resistant to chronic restraint stress-induced lymphocyte reduction, showing that in this condition, stress modulates the immune system through a TLR4-dependent mechanism [110].

In summary, data show that TLRs are involved in the inflammatory response caused by stress. Thus, it seems that innate immunity participates in the neuroinflammation induced by stress, which opens new lines of research. Taking into consideration that the immune response occurs early after the brain injury, this is a new and promising line of research, which deserves attention due to its therapeutic potential.)

Stress effects on the gastrointestinal system

Apart from the actions on the immune system, psychological stress is widely accepted as trigger and/or modifier of the clinical course of a variety of gastrointestinal diseases including the inflammatory bowel disease (IBD). In this respect, it has been shown that immobilization stress induces macroscopic and histological colonic inflammation, increasing iNOS activity and membrane lipid peroxidation and increasing COX-2 expression [111]. Also, it has been shown that exposure to immobilization stress induces weight loss and neutrophil infiltration in the colonic mucosa. Interestingly, these effects are accompanied by a morphological and functional alteration of the colonic epithelial barrier, allowing the pass of microflora from the intestines to other organs such as mesenteric lymph nodes, liver and spleen [111].

In addition, showing again the importance of the actions of the stress on the immune system, it has been described that immobilization stress induces a decrease in the levels of colonic immunoglobulin A (IgA). Secretion of IgA represents a first line of defense against pathogens in the mucosal surfaces by means of, among other mechanisms, agglutinating bacteria and preventing them from binding to intestinal epithelial cells. Therefore, a decrease in the amount of IgA in the colonic lumen could contribute, together with an increased colonic permeability related to tight junctions (TJs) disruption, to bacterial translocation and increased antigen uptake.

Summarizing this, growing evidence from experimental studies is supporting the concept that psychological stress can lead to acute intestinal inflammatory response and barrier dysfunction, resulting in bacterial translocation and enhanced uptake of luminal antigens, which, consequently, are associated with maintained stimulation of lamina propria and submucosa immune cells, and finally with chronic inflammation.

It is important to point out that the pro-inflammatory actions of the stress on the intestinal mucosa and the subsequent intestinal barrier dysfunction may have effects not only on the prognosis of gastrointestinal disorders, but also in other pathologies with an inflammatory component. For instance, it is well known that the inflammation is an important component of the stroke damage, and also that infections are the leading cause of death in the post-acute phase of this pathology. The intestinal dysfunction induced by stress has been related with the bacterial translocation detected in a model of immobilization stress, worsening the experimental stroke outcome [109], and bearing in mind that CNS injury significantly increases susceptibility to infection, the pharmacological modulation of this pathway represents a possible therapeutic approach in stress-related disorders, and particularly in CNS disorders such as brain ischemia. Furthermore, long time exposure to stress is known to increase the onset and course of cardiovascular diseases, immunological disorders and pathophysiological consequences of normal aging. The inability to cope with life events, which leads to the hyper secretion of corticosteroids, imposes an increased risk for depression, as well as increased abdominal obesity, osteoporosis and cardiovascular problems [112].

Further investigation is required to discover the mechanisms involved in these gastrointestinal effects. However, it is known that stress-related factors, such as CRH and GCs can increase intestinal permeability. Consequently, a possible explanation for the effects of the stress on the intestinal integrity can be the increase in CRH and GC levels induced by stress. Nonetheless, there are other stress-related factors that can be playing a role in the stress actions on the digestive system. These can be, among others, the release of pro-inflammatory molecules such as cytokines and prostaglandins, and the activation of the sympathetic nervous system (SNS).

Interestingly, as it has been described in brain, stress also leads to an early induction of PPARgamma expression and 15d-PGJ2 synthesis in the colon (probably as a compensatory mechanism), and  the stress-induced inflammation and dysfunction of the intestinal barrier is prevented with both natural and synthetic PPARgamma ligands (i.e. 15d-PGJ2 and rosiglitazone) [111]. In consequence, the PPARgamma pathway represents not only a promising therapeutic approach for the treatment of the actions of the stress on the CNS, but also to prevent the effects of the stress on the digestive system.

5. Conclusion

The study of the brain response to stress (acute and chronic) is of great importance for several main reasons: first, because stress underlies any pathological condition in humans, therefore, all diseases carry a certain degree of stress; second, because response to stress is a defensive mechanisms: It is a physiological process, at least initially, and it needs to be conserved and not abolished with widespread blocking of adrenal function; third, in the recent years data from many research groups indicate that in the brain, stress produces a response comparable to the one that takes place in many neurodegenerative diseases (excitotoxicity, inflammation, and eventually cell death); fourth, there are specific psychiatric disorders caused by long time or high intensity stress exposure, the so-called post-traumatic stress disorder, but others are related to exposure to stressful situations (mainly depression); furthermore, stress modify the onset or severity of many other pathologies (cardiovascular, gastrointestinal); finally, a compensatory mechanisms has been described to control inflammatory responses in brain and other organs after stress exposure (Figure 1).

pro- and anti-inflammatory effects stressFigure 1. Brain and other organs after stress exposure. Pro- (in blue) and anti-inflammatory (in green) pathways in the brain and the digestive tract after stress exposure (see text for details). Abbreviations used: COX-2, Cyclooxygenase 2; 15d-PGJ2, 15-deoxy-Prostaglandin J2; EAA: Excitatory amino acids; GC: Glucocorticoids; iNOS, Inducible nitric oxide synthase; NF-kappaB, Nuclear factor kappa B; PPAR, Peroxisome proliferator activated receptor.

Overall, data reviewed here indicate that excitatory amino acids and consequent NF-kappaB activation cause the expression and activation of iNOS and COX-2 in cerebral cortex and hippocampus, and support a possible neuroprotective role for the specific inhibitors in these situations. Taking into account the role of these enzymes as initiators of the excessive glutamate and TNF-alpha release, the use of drugs to reduce their action might be useful to minimize or even prevent brain damage in humans. Also agents that potentiate the anti-inflammatory pathway 15d-PGJ2/PPARgamma might be useful to control stress-derived consequences in brain. The experimental tools tested so far should be directed to design molecules that could be administered to humans with stress of long duration or intensity. In conclusion, it seems that a new pharmacological approach is emerging to reduce the accumulation of oxidizing molecules in the brain that occurs after prolonged exposure to stress. Ongoing research should verify the validity of these new drug categories used alone or in combination with antidepressant, anxiolytic and neuroprotective properties currently available.

Nonstandard Abbreviations: ACTH, Adrenocorticotropic hormone; CNS, Central nervous system; CRH, Corticotrophin release hormone; 15d-PGJ2, 15-deoxy-prostaglandin J2; GCs, Glucocorticoids; COX-2, Cyclooxygenase 2; IL, Interleukin; iNOS, Inducible nitric oxide synthase; MCP, Monocyte chemotactic protein; NA, Noradrenaline; NF kappa B, nuclear factor kappa B; POMC, Pro-opiomelanocortin; PG, Prostaglandin; PPAR, Peroxisome proliferator activated receptor; PVN, Paraventricular nucleus; SNS, Sympathetic nervous system; TLRs, Toll-like receptors; TNF, Tumor Necrosis Factor

Author(s) Affiliation

BG Pérez-Nievas, JR Caso, B García-Bueno, JLM Madrigal & JC Leza – Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); Instituto de Investigación Hospital 12 de Octubre (I+12), Madrid, Spain


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