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Is Survival Possible Without Arachidonate Metabolites in the Brain During Systemic Infection?

Ji Zhang and Serge Rivest

Laboratory of Molecular Endocrinology, Centre de Recherche de l’Université Laval and Department of Anatomy and Physiology, Laval University, Québec City, Québec, Canada G1V 4G2

	Abstract

 
The central nervous system mediates a coordinated set of biological responses during systemic immune stimuli. These responses are essential for the organism to eliminate invading pathogens and restore health. Coincidentally, centrally produced prostaglandins play a determinant role in activating the neuronal circuits involved in the control of autonomic functions.

	Introduction

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

 
Inflammation is a general name for reactions occurring after most kinds of tissue injuries, infections, or immunological stimulations as a host defense against foreign or altered endogenous substances. The local inflammatory reaction is characterized by an initial increase of blood flow to the site of injury, enhanced vascular permeability, and selective accumulation of different effector cells from the peripheral blood to injured regions. These cells, mostly circulating neutrophils and monocytes and locally resident macrophages, together mount a rapid inflammatory response that is characterized by, among other features, the secretion of cytokines. Their secretion into the bloodstream is a key step in triggering the neuronal activity and subsequent neurophysiological responses that take place during systemic and localized tissue insults. Cytokines influence many neuroendocrine systems, the most prominent of which is the activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of ACTH and glucocorticoids. Once present in the bloodstream, these cytokines also have the ability to increase body temperature (fever) and cause sickness behavior. The proinflammatory cytokine IL-1, especially its ß form, is probably the most important molecule capable of modulating cerebral functions during systemic and localized inflammation. Systemic IL-1ß injection activates the neurons involved in the control of autonomic functions, and neutralizing antibodies or IL-1 receptor antagonists are capable of preventing numerous responses during inflammatory stimuli. Studies in IL-1ß-deficient mice have, more recently, provided solid and compelling evidence supporting the critical role played by this cytokine in neural-immune interaction.

Other cytokines implicated in neuroendocrine and febrile responses include TNF- and IL-6. Like IL-1ß, intravenous TNF- injection has a profound influence on the brain, fever, and hormones of the HPA axis. In contrast, the role of IL-6 in neuroendocrine and febrile responses is quite controversial. IL-6 has been defined as one of the principle endogenous pyrogens from the observation that IL-6-deficient mice were unable to develop normal fever in response to lipopolysaccharide (LPS) and IL-1ß (3). It has also been demonstrated that prostaglandins (PGs) mediate IL-6-induced fever and activation of the HPA axis, but IL-6 is unable to stimulate PG formation in the brain (6). However, cyclooxygenase (COX)-2-deficient mice do not develop fever in response to intracerebroventricular IL-6 injection (C. Blatteis, personal communication).

	Possible pathways by which circulating IL-1ß signals the brain

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

 
The transport of soluble substances across vascular compartments occurs via either paracellular or transcellular mechanisms. Within the cerebrovasculature, the paracellular route is particularly impermeable due to the presence of the blood-brain barrier (BBB). The BBB consists primarily of nonfenestrated endothelial cells that are connected by tight junctions. Furthermore, the large molecular sizes (13–15 kDa) and the hydrophilic nature of cytokines preclude their transcellular movement by simple diffusion to any appreciable extent, and early studies concluded that the BBB was impermeable to IL-1ß (1). It is nevertheless possible that endogenous cytokines diffuse across the BBB during extreme periods of fever or in the presence of high levels in plasma over a long period of time (2).

Regions relatively devoid of BBB permit cytokine interaction with the neuronal elements. The circumventricular organs (CVOs) contain capillaries with rather greater permeability than the rest of the central nervous system (CNS), and the vascular density in these regions is extraordinarily high. Therefore, the CVOs have been proposed as potential sites of action, in particular the structure lining the anteroventral third ventricle region, namely the organum vasculosum of the lamina terminalis (OVLT) (2). The subfornical organ (SFO), median eminence, and area postrema (AP) are the other potential target CVOs. On the other hand, a medullary group of cells may play an important role in processing visceral sensory information carried out by the vagus and glossopharyngeal nerves. The vagus nerve has indeed been proposed to provide a rapid communication pathway for cytokine signaling between the periphery and brain, but this depends on the doses and route of administration (2, 5).

On the other hand, a strong body of evidence now supports the concept that cytokines, particularly IL-1, act on the microvasculature with consequent release of local signaling molecules, namely PGs. Indeed, brain microvessels exhibit constitutive expression levels of IL-1 type 1 receptor transcript, and systemic IL-1ß injection causes a rapid and profound transcriptional activation of the gene encoding COX-2 in cells lining the CNS blood vessels (12). Circulating IL-1 also induces microsomal PGE synthase (mPGES), which colocalizes with COX-2 in the perinuclear region of the cerebral endothelium (4, 14).

	Biosynthesis of PGs

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

 
Prostanoids are a group of 20-carbon unsaturated fatty acid derivatives that are produced via a complex enzymatic cascade. First, COX activity adds molecular oxygen to the unsaturated fatty acid arachidonic acid, generating PGG₂. PGG₂ is then converted to PGH₂ by the peroxidase activity of the enzyme. Once generated, PGH₂ is rapidly converted to other PGs (PGD₂, PGE₂, PGF₂), prostacyclin (PGI₂), and thromboxane A₂ (TxA₂) by tissue-specific synthases. PGE synthase has recently been identified and designated as mPGES and cytosolic PGES. These molecules or their derivatives interact with specific receptors to modulate cell function. The diversity of the tissue-specific synthases and receptors gives rise to a wide range of potential biological functions for the prostanoids. PGG, PGH, PGI, and TxA are chemically unstable and are degraded into inactive products under physiological conditions, with a half-life of 30 s to a few minutes. Other PGs, although chemically stable, are metabolized quickly. It is therefore believed that prostanoids work locally, acting only in the vicinity of the site of production to serve as potent autocrine and paracrine mediators in a wide variety of physiological processes. Although PGE₂ rises in blood promptly after the entry of microorganisms or in response to the endotoxin LPS and cytokines, it is now generally accepted that the PGE₂ detected in the brain is not derived from the blood but is rather produced directly within the CNS.

It is therefore proposed here that circulating LPS and cytokines bind to their cognate receptors onto endothelial and/or monocytic cells lining the BBB, which leads to proinflammatory signaling and transcription of the enzymes responsible for PGE₂ formation in the cerebral tissue. It is interesting to note that systemic inflammatory insults induce COX-2 and mPGES in a rather nonspecific manner across the cerebral blood vessels and small capillaries (Fig. 1), whereas the neuronal activity is limited to selective nuclei, including the endocrine hypothalamus (Fig. 2). It is thus possible that expression of specific PGE₂ receptors within parenchymal cells adjacent to the site of production determines the action of the PG in the brain.

View larger version (41K): [in this window] [in a new window]   FIGURE 1. Representative example of the distribution of cyclooxygenase (COX)-2 transcript in the rat brain after sterile local inflammation induced by intramuscular administration of turpentine (50 µl/100 g body wt). Animals were killed 6 h after injection of turpentine or its vehicle solution into the left hindlimb. These rostrocaudal coronal sections (30 µm) exhibit positive signals on X-ray films (Biomax) for COX-2 mRNA throughout the brain microvasculature and other nonparenchymal structures, including the choroid plexus and the leptomeninges of turpentine-treated rat. 4V, fourth ventricle; AQ, aqueduct; BLA, basolateral nucleus of the amygdala; bv, blood vessels; Cer, cerebellum; CP, caudate putamen; DG, dentate gyrus; DVC, dorsovagal complex; Hip, hippocampus; IPN, interpeduncular nucleus; LGc, lateral geniculate complex; LV, lateral ventricle; MGv, medioventral geniculate nucleus; PB, parabrachial nucleus; PG, pontine gray; Pir, piriform cortex; VLM, ventrolateral medulla. Reprinted from Ref. 6, with permission.

View larger version (47K): [in this window] [in a new window]   FIGURE 2. Demonstration of EP4 mRNA-activated neurons (using c-fos-immunoreactive protein as an index of cellular activation) to intravenous IL-1ß administration in the hypothalamic paraventricular nucleus (PVN), nucleus of the solitary tract (NTS), and caudal ventrolateral medulla (cVLM). Animals were killed 3 h after injection of the proinflammatory cytokine. Immunocytochemistry (Fos protein, stained nucleus) was performed on the same brain sections (30 µm) before in situ hybridization histochemistry (EP4 mRNA, silver grains). High-power brightfield photomicrographs of right column were taken respectively from the sections depicted by the middle column. Solid arrows show EP4 cells expressing the immediate-early gene Fos-ir in their nuclei. Magnification of left and middle columns, x25; right column, x250. Reprinted from Ref. 15, with permission.

	PGE2 sites of action

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

2

3

In 1988, the distribution of [³H]PGE₂ binding sites, presumably PGE₂ receptors, was first demonstrated in the monkey diencephalon, which was followed by more detailed analysis of [³H]PGE₂ binding sites in rat brain. PGE₂ binding sites were located in a number of discrete brain regions, including thalamic and hypothalamic nuclei, ventral hippocampus, central gray, superior colliculus, parabrachial nucleus, locus coeruleus (LC), raphe nuclei, spinal trigeminal nuclei, and nucleus of the solitary tract. In situ hybridization was thereafter used to determine the exact distribution of each PGE₂ receptor subtype. The hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus exhibited EP₁-expressing cells, but a wide distribution was found for the gene encoding the EP₃ subtype. We (15) and others (10) have reported a very distinct pattern of EP₂- and EP₄-expressing neurons throughout rat brain; namely, EP₂ receptor mRNA was detected in the bed nucleus of the stria terminalis, lateral septum, SFO, ventromedial hypothalamic nucleus, central nucleus of the amygdala, LC, and AP, whereas EP₄ receptor transcript was located mainly in regions involved in the control of neuroendocrine and autonomic activities. Moderate doses of LPS or IL-1ß activate EP₄ neurons (Fig. 2), and this activation is prevented when animals are pretreated with COX inhibitors.

All four PGE₂ EP receptor mRNAs are expressed in the anteromedial preoptic region that plays a crucial role in the febrile response (10, 15, 16). Among these, only EP₄ receptor mRNA is strongly expressed throughout the PGE₂-sensitive regions, including the OVLT, ventromedial preoptic nucleus (VmPO), and median preoptic nucleus. These EP₄-expressing neurons are also activated by systemic inflammation, whereas EP₂ (15) and EP₃-positive neurons (10) do not respond. EP₁ receptor mRNA is present in PGE₂-sensitive regions, but its expression level is weak. This led us to believe that EP₄ may be the key binding and functional receptor for PGE₂ in the brain to activate the circuits involved in the autonomic control.

Nevertheless, pharmacological and genetic mutation experiments suggest otherwise. Drugs with agonist and antagonist properties for each EP receptor were used in rats (9). Intracerebroventricular injection of 17-phenyl--trinor-PGE₂ (an EP₁ and EP₃ receptor agonist) but not butaprost, M&B28767, or 11-deoxy-PGE₁ (EP₂, EP₃, and EP₄ receptor agonists, respectively) induced fever, and SC19220 (an EP₁ receptor antagonist) prevented the febrile response to PGE₂. Another pharmacological study indicated that EP₂ and/or EP₃ receptor might be the receptor(s) necessary to produce fever (11). In mice bearing genetic deletions of the EP_1–4 receptors, only EP₃-knockout animals failed to show the early phase of fever (up to 1 h) after intravenous LPS or intracerebroventricular PGE₂ (13). It is important to note, however, that EP₄-deficient mice do not survive and have to be intercrossed in a different background. It is therefore quite difficult to compare them with the other gene-deficient mice, and inducible EP₄ knockout mice will be essential to clearly define the role of this receptor in the brain of mature animals. The relative lack of specificity of EP₄ antagonists and agonists in the species studied may also explain the pharmacological data. It is nevertheless possible that the anatomy and circuits unraveled by functional indices of neuronal activity have little to do with the physiological outcomes, namely fever and increased activity of the HPA axis.

	Functional circuits by intraparenchymal PGE2

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

 
Without such anatomic work, however, it is not possible to clarify the exact pathways and groups of neurons involved in neural-immune interaction. Indeed, the final picture is far from complete at this time. As a working hypothesis, we would like to propose the following cascade of events based on the data described above, with particular emphasis on those generated in this laboratory (Figs. 3 and 4):

View larger version (69K): [in this window] [in a new window]   FIGURE 3. Innate immune response evoked by endotoxic lipopolysaccharide (LPS). LPS is a major component of the outer membranes of Gram-negative bacteria, which is the best-characterized example of innate recognition associated with a robust inflammatory response by phagocytic cells. Secretion of cytokines by circulating monocytes/neutrophils and tissue macrophages by LPS requires a series of mechanisms in cascade, the first step being the binding of the LPS with the serum proteins LPS-binding protein (LBP) or septins. The newly formed complex may then activate different populations of cells by binding to its CD14 receptor and toll-like receptor 4 (TLR4). The latter is the actual signaling receptor for LPS. Two forms of CD14 receptors can be found. The first is present on the surface of myeloid cells (mCD14) and acts as a glycosyl-phosphatidylinositol (GPI)-anchored membrane glycoprotein; the other form is soluble in the serum (sCD14) and lacks the GPI properties, although it can bind LPS to activate cells devoid of mCD14, such as endothelial cells. LBP is not essential for LPS signaling, but the LPS/LBP complex is particularly powerful in activating cells of myeloid origin, i.e., neutrophils, monocytes, macrophages, and microglia. One of the well-known consequences of such activation is the production of proinflammatory cytokines, such as IL-1ß, TNF-, and IL-6. These cytokines may, in turn, bind to their cognate receptors expressed on the surface of cells forming the blood-brain barrier (BBB), but they are not essential for mediating the effects of LPS in the central nervous system. LPS is an exogenous ligand for cerebral tissue that expresses both LPS receptors. See text for details.

View larger version (50K): [in this window] [in a new window]   FIGURE 4. Intracellular mechanisms involved in the effects of circulating IL-1ß on the transcription of COX-2 within an endothelial cell of the BBB. Both MAPKs and NF-B pathways are likely transduction/transcription signals in these processes. Prostaglandin E2 (PGE2) is believed to be a key mediator that diffuses throughout the parenchymal brain and neurons that control fever and the hypothalamic-pituitary-adrenal axis. The ligand may activate neurons directly by interacting with its transmembrane EP4 receptor expressed on the surface of key neurons of the hypothalamus and medulla. It may also activate these circuits indirectly by inhibiting their major GABA afferent pathways via the EP3 receptor subtype. The subsequent release of glucocorticoids is determinative for the immunosuppression of systemic inflammation and the downregulation COX-2 transcription. Glucocorticoids may increase IB transcription and/or interfere with the NF-B binding ability on COX-2 promoter in cerebral vascular cells. Please note that IL-6 is unlikely to play a major role here, because these intracellular events are prevented in IL-1ß-deficient mice in response to systemic and localized inflammatory insults. IL-6 is also unable to trigger NF-B signaling and COX-2 transcription in the endothelium and pericytes of the cerebral capillaries.

• Endotoxin LPS reaches the bloodstream and binds to the serum protein LPS-binding protein (LBP). The newly formed complex then binds to membrane CD14 and TLR4 receptors located on the surface of myeloid cells, triggering NF-B signaling, nuclear translocation, and cytokine gene transcription (Fig. 4). Pro-IL-1ß and -TNF- have to be cleaved by specific cytosolic enzymes before being transported into the extracellular environment. Once in the bloodstream, both IL-1ß and TNF- can act on distant organs to trigger different physiological responses by binding to type I receptors.
  
• The endothelia and perivascular cells are the most obvious target cells in the CNS, because they constitutively express numerous cytokine receptors and are highly sensitive to low circulating levels of proinflammatory molecules. Please note that circulating LPS is also a direct ligand for these cells and that the release of circulating cytokines is not a prerequisite for LPS activation of the endothelial and perivascular cells lining the BBB.
  
• Circulating LPS/LBP, IL-1, and TNF initiate COX-2 and mPGES transcriptions through a NF-B pathway that is activated within seconds of ligand/receptor interaction. This leads to PGE₂ synthesis and release by the endothelium and pericytes of the brain capillaries. The PG may therefore diffuse across the brain parenchymal elements and bind to specific EP receptors at the surface of the neurons controlling the autonomic functions (Fig. 4).
  
• Whether one or more EP receptors participate in the neuronal response to PGE₂ is still a matter of great debate, but the neuroanatomy weighs in favor of the EP₄ receptor subtype. This receptor is found in key regions that control fever, HPA axis activity, and other autonomic functions. EP₄-expressing neurons are activated (as revealed by spontaneous induction of the immediate-early gene c-fos) in response to centrally injected PGE₂ and systemically administered IL-1 and LPS. Selective and nonselective COX inhibitors have the ability to prevent such functional activation of these neurons. EP₄-expressing neurons display an integrated circuit associated with the control of autonomic functions. The EP₄ receptor is associated with G_s protein and stimulation of cAMP, which is the most potent transduction pathway involved in the release of CRF from the PVN and increase in HPA axis activity. There is also evidence in support of cAMP signaling in thermosensitive neurons of the VmPO.
  
• On the other hand, PGE₂ may inhibit major inhibitory neurons (e.g., GABA) projecting to the nuclei that control the autonomic circuits (Fig. 4). This would explain the data that only EP₃-deficient mice fail to exhibit a febrile response to inflammatory stimuli. This particular receptor is associated with a G_i-coupled protein inhibiting cAMP on its activation, which may take place in GABA neurons that innervate the VmPO and PVN. Obviously, these neurons would not express c-fos or other indices of neuronal activation in response to PGE₂. Functional anatomic data supporting this concept are nevertheless lacking, because we have as yet no reliable tools to assess inhibition rather than stimulation in vivo. If interaction of PGE₂ with its EP₃ receptor blocks the activity of GABA neurons of VmPO and PVN, then the spontaneous induction of immediate-early genes in these regions may be indirectly attributable to GABA inhibition rather than to a direct interaction of PGE₂ with its EP₄ receptor. This is a chicken-and-egg problem that will have to be resolved with appropriate tools and animal models.
  

	Concluding remarks

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

 
More work is clearly needed to unravel the fine-tuning of the circuits and signal transduction pathways that participate in the neural-immune interface. There is, however, no doubt that PGE₂ plays a determinant role in activating or inhibiting the key populations of neurons that are together involved in engaging the physiological responses necessary for the organism to restore health during illness. An appropriate febrile response and a time-dependent release of glucocorticoids are major phenomena in which the brain has a direct impact on the systemic innate immune system. Imbalances in these two regulatory systems are actually becoming hallmarks of autoimmune diseases and neurodegenerative disorders (for review, see Ref. 8). Clarifying the exact mechanisms and circuits that allow such fine neurophysiological outcomes will obviously be essential to designing appropriate therapeutic strategies when dysfunction occurs during the acute-phase response. The best guess at this time leads to the key kinases controlling the proinflammatory signal transduction pathways, COX-2 transcription, and specific PGE₂ receptor subtypes expressed on the surface of the neuronal populations that control endocrine and autonomic functions.

	Acknowledgments

 
Our work in this area is currently supported by the Canadian Institutes of Health Research [formerly the Medical Research Council of Canada (MRCC)]. While a Ph.D. student in this laboratory, J. Zhang held a Studentship from the MRCC. She is now a MRCC postdoctoral fellow at Astra-Zeneca (Montréal, PQ, Canada). S. Rivest is a MRCC Scientist and holds a Canadian Research Chair in Neuroimmunology.

	References

Top Introduction Possible pathways by which... Biosynthesis of PGs PGE2 sites of action Functional circuits by... Concluding remarks References

 

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