Mechanisms of Immune Signaling to the Brain

Signals generated in response to immune challenge, like other viscerosensory stimuli, take multiple pathways to the brain. These pathways can be broadly subdivided into two categories: neural pathways in which immune-derived signals, such as cytokines interact with peripheral nerves (Goehler, Gaykema, Hansen, Maier, and Watkins 2000), and endocrine-like signals, in which the immune- or pathogen-derived signals circulate in the blood to reach specialized immune-sensitive regions of the brain directly (Banks 2005).

6.2.1 Neural Pathways

Peripheral sensory neurons that respond to inflammation or immune activation are predominantly unmyelinated, small diameter A8 and C fibers. Functionally these immune-responsive fibers can be divided into a group of viscerosensory neurons, associated primarily with the glossopharyngeal and vagus cranial nerves, and nociceptive C fibers associated with somatic and visceral sensory spinal nerves and the trigeminal cranial nerve (Kobierski, Srivastava, and Borsook 2000; Scafers, Svensson, Sommer, and Sorkin 2003; Zhang, Li, Liu, and Brull 2002). The glossopharyngeal and vagus nerves innervate most of the alimentary canal, as well as many other important visceral tissues including lungs and lymph nodes. These tissues are notable as major points of entry for diverse pathogens, and the immune responses nerves that innervate them function to initiate physiological and behavioral responses to homeostatic (visceral) challenges, such as infection. In contrast, activation of somatic nociceptors are involved in exaggerated pain states following inflammation in trigeminal terminal fields such as the eyes, nose, and mouth, and inflammatory mediators produced in damaged or inflamed spinal nerves modulate spinal mechanisms of pain transmission. Immune-responsive somatic nociceptors can then influence arousal states via modulation of central (e.g., spinothalamic) pain pathways.

The glossopharyngeal nerve (the ninth cranial nerve) innervates the posterior two-thirds of the tongue as well as other posterior oral structures. Specialized immune structures including the tonsils are located in this region, thus the glossopharyngeal nerve is well positioned for a role in immunosensory surveillance. In support of this idea, application of either lipopolysaccharide (LPS), an immune stimulant derived from bacterial cell walls, or interleukin-1 (IL-1), a proinflammatory cytokine, to the soft palate (receptive field of the glossopharyngeal nerve) induces a fever that can be blocked by prior section of the glossopharyngeal nerve (Romeo, Tio, Rahman, Chiappelli, and Taylor 2001). In addition to innervating the oral cavity, sensory fibers of the glossopharyngeal nerve innervate the carotid bodies, which consist of a very large collection of chemosensory glomus cells that are sensitive to blood gasses and likely other chemical stimuli in the general circulation. The carotid bodies express IL-1 receptor type 1 immunoreactivity (Wang et al. 2002), indicating that in addition to monitoring stimuli relevant to respiratory reflexes, these structures may also participate in signaling systemic immune-related signals.

The vagus nerve (the tenth cranial nerve), like the glossopharyngeal nerve, is well positioned to interact with pathogen products and immune-derived mediators. Vagus means wanderer and this nerve innervates every internal structure, from the larynx to the colon except the spleen. Internal tissues commonly in contact with pathogens, notably the lungs, gastrointestinal tract, and liver are richly supplied with vagal afferents capable of signaling immune activation in these tissues (Berthoud and Neuhuber 2000). The cell bodies of vagal sensory neurons occupy two ganglia, the nodose (or inferior vagal), and jugular (or superior vagal) ganglia, which lie just outside the caudal cranium. These two ganglia form a complex with the petrosal ganglion, which contains the cell bodies of sensory neurons contributing to the glossopharyngeal nerve. The central projections of these neurons terminate in the dorsal vagal complex of the caudal brainstem (see below). In this way, the vagus nerve is positioned to detect immune signals generated in response to local infection or inflammation in tissues commonly in contact with pathogens.

If vagal sensory nerve fibers function as sentinels for the early activation of brain-mediated host defense responses, then one would expect these fibers to innervate immune tissues, such as spleen and lymph nodes that process early signals from pathogens. Surprisingly, the spleen, which is located in the abdomen, and might be expected to receive vagal innervation, clearly does not (Cano, Sved, Rinaman, Rabin, and Card 2001; Nance and Burns 1989). This may be related to the fact that the spleen is not quite on the first line of defense, but rather operates as a filter for circulating immune and pathogen components. Lymph nodes, however, provide a site of early immune activation, as these are the major locations in which antigen presenting cells interface with the T cells that serve to coordinate immune responses. The lymphatic system comprises an interconnecting network of conducting vessels that carry immune cells and antigens, including microorganisms, from lymph node to node, progressively to the heart, and thereafter into the general circulation. Lymph nodes are innervated by both sympathetic and sensory neuropeptide containing nerve fibers (Felton, Livnat, Felton, Carlson, Bellinger, and Yeh 1984; Popper, Mantyh, Vigna, Maggio, and Mantyh 1988), as well as vagal neurons in the nodose and jugular ganglia (Goehler et al. 2000). These observations underline the idea that a major role for vagal afferents involves monitoring early stage immune activation.

Although the lymphatic system is an important early player in host defense, inhaled or ingested pathogens first interact with epithelial barrier tissue in the lung and gut. The gastrointestinal tract contains abundant immune type tissue and cells including specialized immune tissue, such as lymphoid nodules (which are organized somewhat like lymph nodes) and Peyers patches of the small intestine, which reside directly beneath the epithelium. In addition, macrophages and dendritic cells line the epithelium, and overlie the Peyers patches (Nagura, Ohtani, Masuda, Kimura, and Nakamura 1991). Vagal sensory fibers were found in close association with mast cells (Berthoud and Neuhuber 2000) as well, indicating that vagal sensory neurons occupy a position in which they can respond to proinflammatory mediators produced in response to local infections. This arrangement allows vagal sensory fibers to be rapidly activated in response to pathogens in the gastrointestinal system.

In addition to activating vagal afferents directly, immune-related signals may activate vagal immunosensitive pathways via the chemoreceptive cells located in the vagal paraganglia (see below), and/or similar, vagally innervated structures, the neuroepithelial bodies, which are found in lung airways (Adriaensen, Timmermans, Brouns, Berthoud, Neuhuber, and Scheuermann 1998). The vagal paraganglia are collections of glomus cells interspersed throughout the vagus nerve, which are innervated by vagal sensory neurons (Berthoud, Kressel, and Neuhuber 1995). Vagal paraganglia are penetrated by blood and lymph vessels, suggesting that these structures are likely monitoring substances circulating in body fluids. Glomus cells of vagal paraganglia, like those of the carotid bodies, express IL-1 receptors (Goehler et al. 1997; Wang, Wang, Duan, Liu, and Ju 2000). Immune cells expressing LPS-induced IL-1 immunoreactivity codistribute with these glomus cells expressing IL-1 receptors (Goehler et al. 1999), providing an alternative arrangement whereby vagal sensory nerves may monitor immune-related stimuli circulating in either blood or lymph.

Experimental evidence supporting a functional role for the vagus in immunosensory signaling initially relied on studies that involved cutting the vagus nerve in the abdomen, below the diaphragm (subdiaphragmatic vagotomy). Unfortunately, this is a partial lesion, leaving thoracic structures, notably lung and lymph nodes with intact vagal innervation. However, sectioning the vagus above these structures is only feasible in anesthetized terminal preparations. Consequently, results from vagotomy studies need to be interpreted carefully. Findings from these studies have shown that vagotomy can block or attenuate a wide range of illness responses (Goehler et al. 2000 for review), including hypersomnolescence (Hansen and Krueger 1997; Opp and Toth 1998). In general, the effects of vagotomy are most pronounced when the immune stimulus is presented to peritoneal cavity (Bluthe, Michaud, Kelly, and Dantzer, 1996), and when the dose of stimulant is low (Hansen, O'Conner, Goehler, Watkins, and Maier 2001). These findings suggest that the vagus nerve may contribute to the signaling of immune activity locally in visceral tissues, and that higher doses of immune stimulants such as cytokines recruit additional immunosensory pathways associated with the brain, e.g., brain barrier tissues (see below). Additionally, or alternatively, vagal sensory nerves left intact (innervating thoracic structures including lung and lymph nodes) may contribute to immune-to-brain signaling following subdiaphragmatic vagotomy.

Further evidence for a vagal immune to brain signaling pathways is provided by findings that vagal sensory neurons respond to injections of cytokines such IL-1 (Ek, Kurosawa, Lundeberg, and Ericsson 1998; Goehler, Gaykema, Hammack, Maier, and Watkins 1998; Niijima 1996), as well as LPS (Gaykema et al. 1998), staphylococcus enterotoxin B (SEB), a product of gram positive bacteria (Goehler et al. 2000), and live bacteria in the lower gut (Goehler, Gaykema, Opitz, Reddaway, Badr, and Lyte 2005). Interestingly, cells in the nodose ganglia express mRNA and protein corresponding to the TOLL-like receptor 4 (TLR4), a pathogen receptor sensitive to bacterial LPS (Hosoi, Okuma, Matsuda, and Nomura 2005). From the study it was not possible to know the cell type expressing TLR4, which could be satellite cells, resident immune cells, or vagal sensory neurons. Nonetheless, taken together these studies indicate that vagal sensory neurons are likely to be sensitive to a wide variety of pathogenic or immune-derived stimuli.

6.2.2 Endocrine-Like Pathways: Immune Sensing Within the Brain

Although the brain is protected by the blood-brain barrier from diffusion of large lipophobic molecules, such as cytokines, several mechanisms exist that allow circulating cytokines to interact with specialized brain tissue and thereby signal the brain regarding the status of peripheral immune activation. Because cytokines are relatively large, lipophobic proteins, they cannot diffuse passively into the brain. Consequently, most of the pathways identified to date that support direct action of peripherally generated cytokines on the brain involve interactions of cytokines with receptors on cells outside of the blood-brain barrier. Such brain-associated immunosensory tissues include meninges, choroid plexus and endothelium, associated with the blood-brain barrier, as well as specialized brain regions called circumventricular organs (CVOs) and the ventricular ependyma.

The meninges form the outer coverings of the brain, as well as provide the outer structure of sinuses and the fourth ventricle. Meninges contain immune cells, primarily dendritic-like cells and macrophages (McMenamin 1999). These cells can respond directly to pathogens, via their expression of receptors for pathogen products or structural components, or indirectly via their expression of receptors for cytokines. Meningeal cells respond to both central and peripheral immune activation with the expression of cytokines, notably IL-1 (Vernet-der Garabedian, Lemaigre-Dubreuil, and Mariani 2000). The choroid plexus is best known for its role in the production of CSF, but it also contains abundant immune cells. Like those within the meninges, these cells are primarily dendritic cells and macrophages (McMenamin 1999), and express both cytokines and cytokine receptors. Choroid plexus is distributed throughout the ventricular system, and with the meninges, likely provides a significant contribution to the production of cytokines that may access brain regions involved in the regulation of sleep via circulation in the cerebrospinal fluid, via volume transmission in the brain (Konsman, Tridon, and Dantzer 2000) or via accessing the CVOs (see below).

The ventricular ependyma consists of cells lining the walls of the ventricular system. As such they are in contact with substances, including cytokines, present within the cerebrospinal fluid throughout the brain and spinal cord. The cells possess cilia, a typical characteristic of sensory cells (e.g., hair cells, photoreceptors, taste cells and olfactory receptors). They express IL-1 receptors (Ericsson, Liu, Hart, and Sawchenko 1995), and respond to intracerebroventricular injection of LPS or IL-1 with the expression of c-Fos protein (Goehler 2003), an activation marker for many cells. These observations are consistent some kind of immunosensory role for these cells. The mechanisms by which they interface with neural, or glial, elements are unknown, but may involve direct interactions with hypothalamic neurons (Carpenter and Sutin 1983).

Endothelium consists of the luminal lining of cells within blood vessels, rendering them in contact with virtually every circulating substance, including those derived from immune activation such as cytokines. Endothelial cells express a diverse array of substances and receptors, including receptors for IL-1, IL-6, and interferons, which have been implicated in modulation of sleep (Opp 2005) and they also express enzymes necessary for producing prostaglandins. Prostaglandin E2 (PGE2) is strongly implicated in the mediation of several illness responses, including fever and activation of the HPA axis, based on the observations that anti-inflammatory drugs that prevent the synthesis of prostaglandins prevent these responses to systemic cytokine treatment. Compelling evidence indicates that PGE2 produced in endothelial cells contributes to actions of circulating IL-1 (Ericsson, Arias, and Sawchenko 1997). For instance, IL-1 receptors are codistributed in endothelial cells with synthetic enzymes for PGE2 and this codistribution occurs in areas of the brain in which nearby neurons respond to IL-1 (as assessed by induction of activation markers), express PGE2 receptors (EP3), and have been previously implicated in the mediation of illness responses. These regions include the area postrema, nucleus of the solitary tract, and ventrolateral medulla of the caudal brainstem, as well as midline thalamic nuclei and the preoptic area in the forebrain. Thus, immunosensory endothelial cells that express IL-1 receptors can release PGE2 to into the adjacent brain parenchyma to activate neurons that mediate brain responses to immune activation. In this way, prostaglandins represent important diffusible substances that are released via the actions of cytokines circulating within the brain vasculature.

Circumventicular organs, the area postrema, organum vasculosum lamina terminalis (OVLT), subfornical organ (SFO), and median eminence, are situated along the brain ventricles (hence the name) at different locations throughout the neuraxis. The blood-brain barrier is weak within these structures, allowing access to circulating substances excluded from the brain parenchyma. Like the meninges and choroid plexus, CVOs contain numerous immune cells. However, in CVOs, immune cells intersperse among neurons. This arrangement allows for the possibility that immune cells in CVOs respond to circulating substances not accessible to neurons in the brain parenchyma, and signal adjacent neurons via a local, or paracrine kind of mechanism. In addition, IL-1-expressing dendritic like cells in the area postrema make direct contact with axons and dendrites of neurons in the area postrema, providing a direct pathway by which those neurons could activate brain neurocircuitry subserving illness responses (Goehler, Erisir, and Gaykema 2006). This type of interaction may allow for a more specific kind of activation, in that activated immune cells could interface with specific neurons within the CVO that project to and activate specific regions of the brain, allowing for high selectivity in illness responses.

Although cytokines cannot passively diffuse into the brain, an active transport mechanism for circulating cytokines carries them across the blood-brain barrier (Banks 2005). Thus, active transport constitutes an additional mechanism for signal transduction of circulating cytokines, and because its relevance may be selective for certain cytokines, such as IL-6, may provide one mechanism by which different cytokines exert effects on the brain.

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