[neuroimmune biology] the brain and host defense volume 9 || central pathways of immunoregulation

101The Brain and Host DefenseCopyright © 2009 by Elsevier B.V. All rights of reproduction in any form reserved.2010

Central Pathways of Immunoregulation

Kathryn M. Buller Clinical Neuroscience, University of Queensland Centre for Clinical Research, Herston, Queensland, Australia

Chapter 9

1 CENTRAL PATHWAYS OF IMMUNOREGULATION

Defining the central neural pathways that allow neuro-immune interactions to take place is paramount in deci-phering how the brain coordinates specific components of the immune system. At the interface of the immune and central nervous systems are the pro-inflammatory cytokines, interleukin-1 β (IL-1 β ), interleukin-6 (IL-6) and tumor necrosis factor- α (TNF α ) [1 – 3] . During an acute phase response to an immune challenge such as an infec-tion, inflammation or tissue injury, pro-inflammatory cytokines are released systemically by immune cells and can, in sufficient concentrations, stimulate central neural pathways which in turn orchestrate endocrine, behavioral and autonomic responses [1 – 8] . The bidirectional commu-nication between the central nervous and immune systems relies on an extensive neural network. This central network is being elucidated increasingly from studies examining responses following systemic administration of pro-inflam-matory cytokines. In particular, IL-1 β has arguably been the most studied, and the pathways and mechanisms by which this cytokine is involved in generating neuroimmune responses is the focus of this chapter.

2 THE PARAVENTRICULAR NUCLEUS AND IL-1 β -INDUCED HPA AXIS RESPONSES

The ascending and descending neuroimmune pathways that transmit IL-1 β signals are exemplified by the central pathways that converge on, or diverge from, the paraven-tricular nucleus (PVN). Ascending pathways can trigger coordinated neural networks important in generating hypoth-alamo – pituitary – adrenal (HPA) axis responses [9 – 12] . Situated in the medial parvocellular zone of the PVN (mPVN) are the corticotropin-releasing factor (CRF) cells

that represent the apex of the HPA axis. Systemic admin-istration of IL-1 β results in a robust activation of CRF cells [13 – 15] that is integral to the release of CRF into the portal venous system, the production of adrenocorti-cotropic hormone (ACTH) in the anterior pituitary and the subsequent release and pronounced increase in plasma ACTH levels [16 – 20] . ACTH can initiate a glucocorticoid response from the adrenal cortex that can suppress, or at least restrain, the immune response by a glucocorticoid feedback mechanism. This can occur by preventing the overproduction of cytokines and limiting the excessive proliferation of immune cells. The result is that immune responses can be curtailed before they cause tissue damage [21, 22] . Descending neural pathways also emanate from the PVN and, via spinal routes, innervate immune organs and modulate local immune responses. The coordination of these neural networks in response to an immune challenge can be determined by examining the transduction of IL-1 β signals from the periphery to the PVN and back down to the immune end organs.

3 TRANSDUCTION OF IL-1 β SIGNALS FROM THE PERIPHERY TO THE BRAIN

Signaling from the periphery to the brain parenchyma requires immune signals to first cross the blood – brain bar-rier. Consideration of their hydrophilic nature and size lim-itations mean that pro-inflammatory cytokines are unlikely to cross the blood – brain barrier in any significant amount by simple diffusion or saturable carrier-mediated trans-port mechanisms [23, 24] . The processes involved in sig-naling across the blood – brain barrier have not been fully elucidated. However, two key putative mechanisms may account for how large molecular-weight proteins such as IL-1 β (17.5 kDa) can trigger central responses from the periphery.

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SECTION | II Development and Function of the Neuroimmune System102

3.1 The Vagus Nerve

Peripheral cytokine signals may cross the blood – brain barrier via the stimulation of visceral sensory afferent ner-ves; in particular by transmission within the vagus nerve [25 – 30] . Stimulation of receptors in abdominal vagal gan-glia [27, 31, 32] , following intraperitoneal delivery of cytokines, may activate vagal afferents that terminate in a major integratory region, the nucleus tractus solitarius (NTS) of the medulla oblongata ( Figure 9.1 ). It has been shown that HPA axis responses, notably ACTH release, are abolished after subdiaphragmatic vagotomy [25, 28, 29] . In contrast, vagotomy does not affect mPVN CRF c-fos mRNA expression (a marker of cellular activity) [33] and also does not influence ACTH release after intra venous administration of cytokines [18, 34] . Consequently, the transmission of cytokine signals via the vagus nerve depends on the route of administration and appears only to be feasible following intraperitoneal delivery.

3.2 Signaling Via Endothelial IL-1 Receptors

Systemic IL-1 β signals might also reach central neurons indirectly by acting on type 1 IL-1 receptors located on, or closely associated with, endothelial cells lining the blood vessels within brainstem medullary regions [35 – 38] . Although there is some debate as to the identity of the cells that express IL-1 receptors, neurons in the area postrema, NTS and ventrolateral medulla (VLM) are the nodal targets of diffusible substrates produced following IL-1 stimulation. Local stimulation of IL-1 receptors leads to the production and release of prostaglandins that can then diffuse away

and enter the local brain parenchyma to activate nearby area postrema, NTS and VLM neurons ( Figure 9.1 ) [13, 33, 39 – 41] . Prostaglandins are produced by the arach idonic/cyclooxygenase (COX) pathway, which is dependent on two COX enzyme isoforms; constitutive COX-1 and inducible COX-2. During an acute-phase response it is the COX-2 enzyme that is responsible for producing prosta glandins [42, 43] . Systemic IL-1 β induces pervasive COX-2 mRNA in the microvasculature of the brain [40] . In addition, administra-tion of indomethacin, a non-selective COX enzyme inhibi-tor, attenuates IL-1 β -induced c-fos protein expression [13] and CRF mRNA in mPVN CRF cells [33] . The cytokine-induced release of CRF from the hypothalamus and ACTH release from the anterior pituitary can also be blocked by COX inhibition [13, 18, 44 – 46] .

The enzyme COX-2 is concentrated within non-neuronal cells, most likely to be perivascular microglial or endothe-lial cells, closely associated with blood vessels of the area postrema, VLM and NTS [39 – 41] . Dense binding sites for prostaglandins, in particular the prostaglandin E 2 (PGE 2 ) receptor subtype (EP3), have been identified in the area postrema, NTS and VLM regions [36, 47 – 50] . At the brainstem medullary level, inhibition of prostaglandin syn-thesis attenuates neuronal activation following systemic IL-1 β administration [13, 33] . In addition, microinjections of PGE 2 into the VLM lead to the recruitment of medul-lary and PVN neurons [33] . It is notable that perfusion of the PVN with indomethacin does not prevent IL-1-induced activation of the HPA axis [51] and PGE 2 receptor subtypes have not been detected in the PVN [52, 53] . This evidence further supports the notion that initial IL-1 β central sign-aling occurs extrahypothalamically and most likely within the hub of the medulla oblongata.

BNST

mPVN

ME

Anterior pituitary

CeA

PVTPBel

C1

A1

A2

EP3

BRAIN

Vagus nerve

BLOODIL1R1 IL-1β

PGE2

APNTS

C2

VLM

ACTH

FIGURE 9.1 Schematic diagram of a parasagittal view through the rat brain showing putative transduction mechanisms and ascending neuroimmune pathways that converge on the mPVN to trigger HPA axis responses following systemic IL-1 β administration. The inner lines represent ascending neural pathways. A1, VLM A1 noradrenergic cells; A2, NTS A2 noradrenergic cells; ACTH, adrenocorticotropin hormone; AP, area postrema; C1, VLM C1 adrenergic cells; C2, NTS C2 adrenergic cells; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; EP3, prostaglandin PGE 2 receptor; IL-1 β , interleukin-1 β ; IL-1R1, interleukin 1 receptor; ME, median eminence; NTS, nucleus tractus solitarius; PBel, external lateral division of the parabrachial nucleus; PGE 2 , prostaglandin E 2 ; mPVN, medial parvocellular zone of the paraven-tricular nucleus; PVT, paraventricular thalamus; VLM, ventrolateral medulla. Note: The e-book for this title, including full-color images, is available for purchase at www.elsevierdirect.com

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Chapter | 9 Central Pathways of Immunoregulation 103

4 ASCENDING NEURAL PATHWAYS TO THE PVN IMPORTANT IN IL-1 β SIGNALING

Once peripheral IL-1 β signals cross the blood – brain barrier and enter the brain parenchyma, the first neurons recruited within the central nervous system appear to be circumven-tricular neurons in the area postrema and catecholamin-ergic neurons in the NTS and VLM ( Figure 9.1 ). These neuronal populations essentially serve as major integratory sites to relay cytokine signals to higher brain centers and, directly or indirectly, project to the PVN.

4.1 Circumventricular Organs

The area postrema, subfornical organ, median eminence and organum vasculosum of the lamina teminalis are spe-cialized structures that lack a normal blood – brain barrier and sit, as their name suggests, in the major ventricles of the brain. Via fenestrated capillaries, circumventricu-lar organs can potentially monitor circulating levels of cytokines and also allow the passage of certain proteins. Circumventricular neurons are recruited by circulating cytokines, and all these structures have direct or indirect neural connections with the PVN. However, only the area postrema has emerged as a significant circumventricular candidate that contributes to PVN responses after systemic IL-1 β administration (see [54] ).

The area postrema is situated at the dorsal aspect of the caudal medulla oblongata, and is a component of the dor-sal vagal complex. It is unlikely that area postrema neurons project directly to the hypothalamus, but rather they have the potential to signal to PVN CRF cells and contribute to cytokine-induced HPA axis responses indirectly via neuro-nal projections to NTS and VLM catecholamine cell groups [55 – 57] . Type 1 IL-1 receptors (IL-1R1) are concentrated predominantly within the area postrema, choroid plexus and meninges [35, 36, 38, 58] , and the area postrema exhibits pervasive IL-1R1 mRNA expression in the IL-1 β -activated state [35] . After systemic IL-1 β administration, a marked, robust increase in c-fos is evident [13, 59 – 62] . Removal of the area postrema inhibits the IL-1 β -induced elevation of PVN c-fos mRNA and plasma ACTH and corticosterone [62] . Furthermore aspiration of the area postrema reduces c-fos mRNA in the NTS [62] and attenuates noradrenaline levels in the PVN in response to systemic IL-1 β [28] .

4.2 Brainstem Catecholamine Cells

It is well documented that the HPA axis responses to systemic IL-1 β depend on catecholaminergic inputs to the hypothala-mus [14, 15, 63 – 66] . As noted earlier, these neuronal popu-lations in the medulla oblongata represent a key integratory hub for ascending immune signals. Both noradrenergic and adrenergic terminals synapse onto mPVN CRF cells [67, 68] ,

and the sources of cytokine-stimulated catecholamine inputs are the NTS and VLM catecholamine neurons. A systemic bolus of IL-1 β induces a distinct recruitment pattern of NTS A2 noradrenergic, VLM A1 noradrenergic and VLM C1 adrenergic cell groups [13 – 15, 69] ; very few NTS C2 adren-ergic cells are activated by IL-1 β [14, 15] . Interruption of VLM and NTS projections, either by transecting the ascend-ing catecholamine projections from the medulla oblongata to the hypothalamus [14] or by excitotoxin lesions of cell bod-ies in the NTS and VLM cell columns [15] , attenuates IL-1 β -induced PVN responses. In addition, selective depletion of PVN catecholaminergic terminals using the neurotoxin 6-hydroxydopamine significantly reduces IL-1 β -induced mPVN CRF cell recruitment [15] . Interruption of catecho-lamine inputs also attenuates IL-1 β -induced increases in plasma levels of ACTH or corticosterone [63 – 66, 70] .

Furthermore , reciprocal neural connections between the VLM and the NTS [71 – 74] allow neural communi cation between these medullary cell columns. In this context, it is notable that NTS neurons might also influence mPVN CRH cell responses indirectly via VLM projection neurons [15, 75] .

Central pathways originating in the brainstem NTS and VLM catecholamine regions also have pertinent roles in the recruitment of at least three other major brain regions involved in neuroimmune signaling; the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST) and the parabrachial nucleus. These three struc-tures have been described as participating in the elaboration of IL-1 β -induced HPA axis responses, and thus constitute alternative afferent neuroimmune pathways that converge directly and/or indirectly on the PVN.

4.3 Central Nucleus of the Amygdala

Functional attributes of the amygdala have primarily reflected its role as a key limbic site involved in the integra-tion and processing of autonomic, endocrine and behavior-related information [76 – 79] , but it is now apparent that the CeA contributes to the generation of IL-1 β -induced HPA axis responses [69, 75] . The CeA neurons, unlike the other 11 or so amygdala divisions, are robustly activated [13, 14, 69] in response to systemic delivery of IL-1 β . In addition, lesions of the CeA attenuate both mPVN CRF cell responses and ACTH release following systemic IL-1 β administration [69] . However, only a few cell bodies project directly from the CeA to the mPVN [80 – 84] , and this small population is unlikely to account for the degree of loss of HPA axis responses observed following CeA lesions. Consistent with this, IL-1 β -activated neurons in the CeA do not correspond to those that project directly to the PVN [14] . Instead, based on retrograde tracing and bilateral CeA lesion studies, the CeA may influence PVN-mediated HPA axis responses indirectly via projections to the BNST.

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The CeA projects to the dorsal (dBNST) and ventral divi-sions of the BNST (vBNST) [84 – 86] , and cells in both of these divisions are recruited following systemic IL-1 β admin-istration [14, 60, 61, 87] . However, CeA lesions only sig-nificantly reduce IL-1 β -induced c-fos expression within the vBNST, not the dBNST [69] . Also, only cells of the vBNST are recruited following systemic IL-1 β administration and project to the mPVN cell group [88] . Taken together, it is likely that the vBNST serves as a neuroimmune IL-1 β relay for CeA neurons to influence PVN HPA axis reponse.

Although excitotoxic lesions of NTS cells in the brain-stem reduce the number of CeA cells recruited in response to systemic IL-1 β [15] , it is unlikely that this effect is due to the loss of direct NTS projections to the CeA. This is because retrograde tracing studies have shown that the para-brachial nucleus and the paraventricular thalamus (PVT) contribute the greatest complement of direct neural projec-tions to the CeA following systemic IL-1 β rather than the NTS neurons [75] . Thus, the parabrachial nucleus and PVT may act as relay sites for transmitting immune signals from the brainstem to the CeA to help coordinate the elaboration of central immune responses elicited by systemic IL-1 β [75] . The PVT receives afferent inputs from both the lateral parabrachial nucleus and the NTS [89 – 91] , both of which are activated by systemic IL-1 β [13 – 15, 69, 87] .

4.4 Bed Nucleus of the Stria Terminalis

The BNST has a central role in regulating stress responses, including effects on endocrine, immune and autonomic nervous system function [92 – 95] . As noted earlier, only IL-1 β -activated cells located in the vBNST project to the mPVN cell group [14, 88] . Selective BNST lesions that encompass the vBNST reduce not only the expression of ACTH secretagogues [96] , but also the mPVN CRF cell response to systemic IL-1 β [88] . Recruitment of BNST neurons in response to systemic IL-1 β may occur via affer-ent inputs from the CeA and parabrachial nucleus. Like the CeA, neurons of the parabrachial nucleus also innervate the BNST [89, 97 – 99] . Furthermore, lesions of the parabrachial nucleus significantly reduce the numbers of Fos-positive cells observed in both the dBNST and vBNST after systemic IL-1 β [87] , suggesting parabrachial projections recruited by IL-1 β may influence the activation of the BNST.

4.5 Parabrachial Nucleus

Situated in the dorsolateral pons, the parabrachial nucleus consists of three main neuronal groups: the lateral parabra-chial; medial parabrachial; and Kolliker-Fuse nuclei [89] . Systemic immune stimuli lead to the activation of para-brachial neurons, especially in the external lateral division [14, 75, 87, 100 – 102] . The recruitment of parabrachial neu-rons following systemic IL-1 β administration is most likely

to depend on neuronal inputs from NTS and VLM cells [57, 72, 87, 103 – 105] . Moreover, afferent inputs arising in the area postrema might also contribute to IL-1 β -induced lateral parabrachial neuronal responses [57, 99, 103] .

Lesions of the parabrachial nucleus do not appear to affect mPVN CRF cell responses following systemic IL-1 β administration [87] , and instead might have a greater influ-ence on other nuclei such as the CeA and the BNST [87] . Axonal projections from cell bodies in the parabrachial nucleus that terminate in the CeA are recruited by sys-temic IL-1 β [75] . In addition, parabrachial nucleus lesions decrease numbers of Fos-positive neurons in the CeA and BNST after systemic IL-1 β [87] .

Thus , brainstem catecholamine neurons are able not only to relay cytokine signals to the PVN; it is also plau-sible that they indirectly coordinate HPA axis responses via the CeA, BNST and parabrachial nuclei. Other brain regions may well contribute to HPA axis response fol-lowing peripheral cytokine administration; however, the aforementioned regions appear to be the critical candi-dates involved in neuroimmune signaling to induce ACTH release from the anterior pituitary.

5 DESCENDING NEURAL PATHWAYS FROM THE PVN TO IMMUNE END ORGANS

Pro -inflammatory cytokines such as IL-1 β can activate pre-sympathetic areas in the brain, substantiating evidence that the sympathetic nervous system provides a vital neu-ral link between the brain and the immune system. In par-ticular, systemic IL-1 β administration activates descending pathways arising predominantly from pre-sympathetic divisions of the PVN that in turn project to the VLM and the NTS in the brainstem ( Figure 9.2 ) [106] . The PVN, VLM and NTS send neural projections to preganglionic neurons situated in the spinal cord [107 – 111] , and have been reported to influence downstream sympathetic activ-ity including neural transmission to immune organs via sympathetic ganglion connections ( Figure 9.2 ) [112 – 114] . It has been well documented that systemic IL-1 β adminis-tration can regulate the sympathetic nervous system by, for instance, affecting plasma catecholamine levels [115] and sympathetic nerve activity important in modulating periph-eral immune responses [116 – 119] .

6 RECRUITMENT OF PRE-SYMPATHETIC NUCLEI

6.1 Paraventricular Nucleus

In terms of the central command nuclei producing end-organ immune effects, it has been suggested that forebrain, as opposed to spinal and midbrain, connections are

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required for producing excitatory splenic nerve responses following systemic IL-1 β [119] . Evidence suggests that the PVN is a primary pre-sympathetic candidate, since the PVN can modulate systemic IL-1 β -induced effects on the sympathetic nervous system and splenic immune function. The PVN has an excitatory influence on splenic nerve activity [112] , and central administration of CRF (i.c.v.) increases plasma noradrenaline, increases splenic noradrenaline and reduces splenic natural killer cell activ-ity [113, 114] . These effects are blocked by injecting CRF antagonists (i.c.v.) [120] , or by pre-treatment with a gang-lionic-blocking agent consistent with the concept that acti-vation of the sympathetic nervous system plays a key role in PVN-induced effects on immune function [113, 114] .

Reciprocal neural connections exist between the PVN, NTS and VLM [110, 111, 121 – 129] , but a potential mod-ulatory role of the PVN on brainstem nuclei via descend-ing projections has only recently been realized in response to a systemic immune challenge [75] . Excitotoxic lesions of the PVN that encompassed five divisions known to send axons to the brainstem significantly reduced VLM and NTS cell responses to systemic IL-1 β administration [75] . Thus, although this study was important in defining a descending neuroimmune pathway, the specific PVN divi-sions involved and whether the direct and/or polysynaptic descending PVN projections contributed to the brainstem effects could not be deduced. Therefore, we iontophoret-ically deposited a retrograde tracer into the NTS or VLM

and found that, regardless of whether tracer deposits were made in the NTS or VLM, there was a clear predominance of recruited cells in the lateral and medial parvocellular divisions of the PVN that project to the brainstem [75] . Thus, these descending lateral and medial parvocellular PVN pathways are likely to alter brainstem catecholamine and non-catecholamine responses to systemic IL-1 β via direct neural inputs [75] .

6.2 Alternative Descending Pre-Sympathetic Sources

Aside from the PVN, there is evidence that descending pre-sympathetic immune pathways might also originate in the parabrachial nucleus, BNST and CeA.

Unilateral lesions of the parabrachial nucleus cause bilateral reductions in the VLM A1 cell response to sys-temic IL-1 β administration [87] . However, the large majority of parabrachial neurons recruited after IL-1 β are localized in the external lateral division of the parabrachial nucleus – a region that does not directly innervate the ven-trolateral medulla [89, 130] . Instead, it is suggested that a putative descending pathway is likely to be polysynaptic, possibly via direct projections from the nearby Kolliker-Fuse and lateral crescent nuclei to the VLM [131] .

The CeA can also influence VLM A1 cell responses following systemic interleukin-1 β [69], and thus could

BNST

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CeA

PVTPBel

C1A1

A2

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C2

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spleen

thymus

SCG SMG

T1-4 T7-10

ACTH

FIGURE 9.2 Schematic diagram of a parasagittal view through the rat brain and spinal cord. The descending neuroimmune pathways inner lines are the main neural projections believed to be responsible for systemic IL-1 β signals to descend from the PVN to ultimately alter immune end organ responses. A1, VLM A1 noradrenergic cells; A2, NTS A2 noradrenergic cells; ACTH, adrenocorticotropin hormone; AP, area postrema; C1, VLM adrenergic cells; C2, NTS C2 adrenergic cells; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; IL-1 β , interleukin-1 β ; ME, median eminence; NTS, nucleus tractus solitarius; PBel, external lateral division of the parabrachial nucleus; PVN, paraventricular nucleus; PVT, paraventricu-lar thalamus; SCG, superior cervical ganglion; SMG, superior mesenteric ganglion; T 1 – 4 , thoracic levels 1 – 4; T 9 – 13 , thoracic levels 9 – 13; VLM, ventro-lateral medulla. Note: The e-book for this title, including full-color images, is available for purchase at www.elsevierdirect.com

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constitute a pre-sympathetic region. However, whether this VLM A1 response can be attributed to a direct descending pathway is not clear, because the tracing studies report that the CeA primarily innervates the VLM C1 cells [132, 133] . Finally, the BNST has also been reported to send neural projections to the VLM [134] , although the importance of this pathway for central IL-1 β signaling is not known.

7 DESCENDING CONNECTIONS FROM PRE-SYMPATHETIC TO PREGANGLIONIC CELLS

Sympathetic preganglionic neurons in the thoracic spinal cord are located in the central band, which includes four major subdivisions: the intermediolateral cell column (IML); the intercalated nucleus; the central autonomic nucleus; and the lateral funiculus. A major descending path-way to the IML of the spinal cord originates in the PVN [135, 136] . Both the VLM and NTS have neural connec-tions with sympathetic preganglionic neurons located in the thoracic IML [74, 109 – 111, 124, 137 – 141] . Furthermore, a population of PVN neurons innervates both the VLM and sympathetic neurons in the IML [110, 111, 124] . Despite this evidence, very little is known about the spe-cific pathways recruited following a systemic immune challenge. It has been demonstrated that systemic admin-istration of the endotoxin lipopolysaccharide (LPS) elicits Fos expression mainly in putative preganglionic neurons in the thoracic spinal cord from T 3 to T 13 [141, 142] . However, only cells within the dorsal parvocellular PVN division and the rostral VLM that are recruited following systemic administration of LPS are reported to project to sympathetic preganglionic neurons in the IML [141] . It should also be noted that LPS induces the secretion of all three pro-inflammatory cytokines (IL-1 β , TNF α and IL-6) [143] , and therefore it is not possible to differentiate effects of individual cytokines.

8 INNERVATION OF IMMUNE ORGANS BY SYMPATHETIC PROJECTIONS

Sympathetic preganglionic efferent fibers leave the thor-acic segments and terminate primarily in the superior cerv-ical ganglia (SCG), stellate ganglia, superior mesenteric ganglia (SMG) and coeliac ganglia, from which postgan-glionic sympathetic fibers course to their target tissues [135, 136, 144, 145] .

8.1 Innervation of the Spleen

The spleen receives sympathetic efferent inputs from the superior mesenteric and coeliac ganglia [146] that stem

from preganglionic neurons located from the T 7 to T 13 and T 10 to T 13 [147, 148] spinal segments, respectively. Trans-synaptic tracing techniques have confirmed that neurons in the PVN give rise to neural projections to the spleen [147] . Furthermore, we have recently demonstrated that the PVN can influence the IL-1 β -induced activation of brainstem neurons [106] known to project to the spinal cord and ulti-mately the spleen [147] . Nonetheless, whether other pre-sympathetic sites such as the rostral VLM can influence the IL-1 β -induced activation of sympathetic preganglionic neurons and contribute to sympathetic-mediated immune effects remains to be elucidated.

It is clear that systemic IL-1 β can increase splenic sympathetic nerve activity [116, 117, 149] and trigger an immediate increase in noradrenaline release in the spleen [120] , the latter effect being dependent on the integrity of the splenic nerve [120] . Electrical stimulation of the splenic nerve (which consists almost exclusively of post-ganglionic sympathetic fibers) can suppress splenic natu-ral killer cell activity in rats, and this effect is blocked by peripherally acting β -adrenergic blocking agents [112] .

8.2 Innervation of the Thymus

In contrast to the spleen, the thymus is primarily innervated by sympathetic fibers arising from the SCG [150, 151] . The SCG receive preganglionic inputs almost exclusively from the IML in thoracic levels T 1 – T 4 [145] .

Thus there exists a distinct segmental arrangement of neural inputs from the spinal cord to immune end organs. It remains to be determined if each pro-inflammatory cytokine also has a distinct descending “ sympathetic signature ” in order to coordinate specific end-organ immune responses.

9 CONCLUSIONS

Identification of the central command neurons activated after systemic IL-1 β administration, their connectivity with immune end-organs and defining the functional role that they play in regulating the immune system enables us to establish how ascending and descending neural path-ways link the brain and the immune organs. The ascend-ing pathways are relatively well characterized; however, at this time there remains a significant gap in our knowledge of the specific descending pre-sympathetic and ganglionic pathways recruited by pro-inflammatory cytokines. Until these pathways are fully elucidated, it is difficult to define the functional implications of these neural connections on the immune system. Nonetheless, there is clearly a coordi-nated neural network in the brain that is capable of regu-lating, or at least fine-tuning, peripheral immune responses following systemic changes in pro-inflammatory cytokine levels.

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[neuroimmune biology] the brain and host defense volume 9 || central pathways of immunoregulation

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