14

Figure . Schematic depiction of pathways enabling bidirectional interactions between the nervo-us, endocrine, and immune system (modified according (Di Comite a spol., 2007).

lymphatic organs

lymphatic nodes

bone marrow

spleen

thymus

AVP

endocrine organs

gonads

FSH – LHprolactin

adrenal gland

ACTH

peripheral tissues

immune cells

di�use neuroendocrine cells

glucocorticoidscatecholamines

estrogensprogesteronetestosterone

ACh

norepi-nephrine

NPY

neuro-transmitters

15

33. Neuro-endocrine-immune

interactions

The CNS can monitor activities of the immune system mainly via two pathways: humoral and neural (Fig. 1; Dantzer et al., 2000; Elmquist et al., 1997; Goehler et al., 2000; Pavlov et al., 2003). While the humoral pathways are relatively slow and less in-formative regarding the location or source of the immune signals, the neural pathways, on the contrary, are fast and location specific.

Humoral pathwaysCytokines are key messengers involved in the transmission of signals from the

immune to the nervous system (Mantovani, 1999; Sternberg, 1997). They can exert their effect on the nervous system utilizing different routes. Receptors for cytokines are present in many peripheral structures as well as in the CNS (Rothwell and Hop-kins, 1995). Interactions with autonomic nerves (especially the vagus nerve) and with peripheral somatic nerves are discussed bellow. Another route for signal transmissions is represented by an indirect interaction of circulating cytokines with the brain (Li-cinio and Wong, 1997). The brain is informed about cytokines that circulate in the blood and reach the brain circulation at least by three different pathways that may convey information from the immune system to the CNS: a) cytokines can pass the blood-brain barrier (BBB) at the level of circumventricular organs (CVOs) and bind to receptors on macrophages (Buller, 2001); b) circulating cytokines may activate the cerebral endothelial cells, which in turn transmit signals to perivascular macrophages that activate the microglia within the brain parenchyma (Elmquist et al., 1997; Perry, 2004); and c) cytokines may be actively transported by the endothelium across the BBB (Quan and Herkenham, 2002; Turrin and Rivest, 2004). It is important to note that cytokines binding to receptors on macrophages, endothelial cells, or astrocytes induce the production of soluble molecules (e.g. prostaglandins, nitric oxide) that convey the signal from the circulation to the CNS (Konsman et al., 2002; Nadeau and Rivest, 1999; Szelenyi, 2001; Turrin and Rivest, 2004; Watkins et al., 1995). It has been suggested that prostaglandins may also be crucial messengers that constitute links between circulatory cytokines and the CNS (Quan and Herkenham, 2002; Rivest,

16 NEUROBIOLOGY OF SOMATIC DISEASES

2001; Turnbull and Rivier, 1999). In addition, the presence of receptors for cytokines in the non-tanycytic portions of the ependymal lining, the choroid plexus and vascular endothelium, suggests that the endothelial cells might participate in the transmission of immune signals to the CNS (Ericsson et al., 1995; Harre et al., 2002; Turrin and Rivest, 2004; Vallieres and Rivest, 1997). Circulating IL-1� has direct access to cortical brain cells located behind the BBB through a saturable transport system that provides a pathway by which the brain and immune systems interact (Banks et al., 1993). Thus, activation of endothelial cells in the BBB followed by secretion of specific messenger molecules such as prostaglandins, seem crucial for humoral immune-to-brain commu-nication.

Circumventricular organs play a critical role as transducers of information betwe-en the blood, neurons, and cerebral spinal fluid. They permit both the release and sensing of chemical compounds without disrupting the BBB. Therefore they play an essential role in the regulation of diverse physiological functions (e.g. control of the cardiovascular function, body fluid regulation, feeding behavior, and reproduction). Moreover, CVOs are significantly involved in the central immune responses (Buller, 2001; Cottrell and Ferguson, 2004; Ferguson and Bains, 1996; Ganong, 2000). There are two main arguments that support the emergence of CVOs as important CNS structures in the immune regulations: a) all sensory CVOs (the subfornical organ, the organum vasculosum of the lamina terminals and the area postrema) possess receptors for cytokines, i.e. IL-1�, IL-6; TNF that provide a basis for transmission of immune signals to the brain (Ericsson et al., 1995; Nadeau and Rivest, 1999; Roth et al., 2004; Turrin and Rivest, 2004) and b) cells of the CVOs show physiologically relevant mor-phological and electrophysiological changes during the early phase of the immune res-ponse (Cottrell and Ferguson, 2004). Thus, the humoral pathways may convey immune information in certain physiological contexts.

Neuronal pathwaysInformation from the immune system may also reach the CNS via peripheral ner-

ves. Cytokines play a pivotal role in the transmission of signals from the immune system to peripheral nerves. However, other peptides/proteins are also involved in the interaction between the immune and peripheral nervous system. Immune cells are capable of synthesizing many peptide hormones and neurotransmitters, e.g. corticotro-phin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), endorphins, thyroid stimulating hormone, growth hormone, prolactin, substance P, vasopressin, oxytocin, somatostatin, and neuropeptide Y (Savino and Dardenne, 1995; Petrovsky, 2001; Shepherd et al., 2005). These compounds do not act only in a paracrine manner. For example, immune cell-derived �-endorphins might act on opioid receptors on the peripheral terminals of sensory neurons (Blalock, 1994).

Peripheral nerves could receive information directly from specialized immune cells or from sentinel cells, e.g. dendritic cells and subpopulations of tissue fibroblasts. Sen-tinel cells process information about the immune status of surrounding tissue and may consequently transmit these signals to the peripheral nervous system via production of cytokines (Buckley et al., 2001; Kaufman et al., 2001; Smith et al., 1997). It is sugges-ted that sentinel cells might represent an analogy to taste cells. Both, the sentinel and taste cells are in the first line of contact with the chemical stimulus, and respond by

173. Neuro-endocrine-immune interactions

Figure 1. Pathways, which transmit information from the immune system to the brain (A-D).(A) Cytokines (e.g. IL-1, IL-6, TNF) circulating in blood stream influence brain activity via circumventricular organs (e.g. subfornical organ-SFO, organum vascullosum lamine terminalis--OVLT, area postrema-AP) or via interaction with brain endothelial cells.(B) Binding of cytokines (e.g. IL-1) to receptors on vagal paraganglion dendritic cells (grayish cell with protrusions) or directly to receptors of the vagus nerve activate vagus nerve afferents that transmit information to the NTS.(C) Endorphins (�-END) might bind to the endings of somatic afferents and produce an anal-gesic effect.(D) Whether sympathetic nerve afferents are influenced by some compound (?) released from immune cells remains to be investigated. Because the vagus nerve innervates only limited visceral areas, it is possible that information is carried via the sympathetic afferents.

circulation

A

C

B

D

?

somatica�erents

spinal viscerala�erents

dorsal rootganglion

vagalparaganglion

immunecell

IL-1

β, IL

-6TN

F-α

IL-1β

β-END

vagala�erents

NTS

SFO

AP

vaga

l sen

sory

gang

lion

OVLT

dorsal rootganglion

18 NEUROBIOLOGY OF SOMATIC DISEASES

generating a second signal capable of activating neural elements (Goehler et al., 2000).One of the most important visceral sensors is represented by the vagus nerve. It in-

nervates the thorax and abdomen with fibers containing a variety of sensory receptors (Paintal, 1973). The role of the vagus nerve in the transmission of information about peripheral inflammatory processes is well recognized. The data indicate that capsaicin--sensitive afferent fibers of the hepatic vagus nerve constitute necessary components of the afferent mechanism of the first febrile phase (Romanovsky et al., 2000). This is supported by data showing that vagal sensory neurons themselves express mRNA for IL-1 receptors, suggesting a direct reaction of afferent vagal fibers to IL-1 (Ek et. al., 1998). Therefore, cytokines might activate the sensory afferents of the vagus ner-ve, which transmit signals from the immune system to the CNS, particularly to the nucleus of the solitary tract (Maier et al., 1998; Perry, 2004). While the role of the vagus in immune-to-brain communication is quite established (Ek et al., 1998; Goehler et al., 1998), this may be limited to low concentrations of peripheral pro-inflammato-ry cytokines (Hansen et al., 2000). This role may be pertinent to low concentrations of inflammation that can promote tumorigenesis, as described below. Another group of important visceral sensors are paraganglia, which represent structures supporting transmission of information from the immune system to the brain via the vagus nerve (Watkins et al., 1995). Paraganglia, innervated by the vagus nerve, contain cells that express IL-1 receptors. This arrangement represents an important link between the immune and nervous systems (Goehler et al., 1997, 1999). IL-1 receptors appear to be located on dendritic-like cells as well, interdigitating the vagus nerve parenchy-ma (Licinio and Wong, 1997). In the paraganglia, immune cells are activated during inflammation and consequently may stimulate the vagus nerve endings. Therefore, immune cells of paraganglia are responsible for the indirect activation of the vagus nerve (Goehler et al., 2000). Interestingly, some data suggest, that the carotid body (paraganglion involved in the monitoring of blood oxygenation), also expresses cyto-kine receptors for the monitoring of immune signals (Wang et al., 2002a). The vagus nerve does not innervate all visceral organs. Therefore it can be hypothesized that sympathetic sensory (afferent) fibers might also transmit certain immune-related infor-mation from the vagus innervation-free visceral regions of the body. While the vagus nerve mediation of immune signals from the visceral regions is well characterized, the role of the cutaneous sensory nerves in transmission of immune signals is less clear. However, experiments using bacterial lipopolysaccharide-induced inflammation and local anesthesia indicate that cutaneous sensory nerves can modestly participate in the transmission of inflammatory information to the CNS (Roth and De Souza, 2001). Tactile hypersensitivity during inflammatory diseases and observations in patients with leprosies also suggest a possible role of cutaneous sensory afferent fibers in trans-mission of signals from the immune system to the CNS (Hermann et al., 2005). It is presumed, that disruption of sensory C-fibers and sympathetic innervation in leprosies is responsible for the loss of anti-inflammatory immune-nervous system communicative and modulatory circuits (Rook et al., 2002).

Messages conveying pathways from the brain to the immune systemThe CNS has capacity to deliver neurotransmitters and neuropeptides to all tissues

in the body. For a long time, the immune system was considered an exception to this

193. Neuro-endocrine-immune interactions

rule. However, it is now clear that the thymus, spleen, and other lymphoid organs are also innervated by the nervous system. Therefore the nervous system, including the brain and the peripheral nervous system, can stimulate or inhibit activities of the in-nate and adaptive immune systems via two ways, neural and humoral (Fig. 2; Berczi, 2001; Brogden et al., 2005).

Humoral pathwaysThe main messengers of humoral communication between the brain and the immu-

ne system are hormones released from adenohypophysis (Berczi, 2001). It was shown that after parturition, the function of the bone marrow, the thymus and the ma-intenance of immunocompetence, all became dependent on the pituitary prolactin (PRL) and growth hormone (GH). Thyroid stimulating hormone modulates immune functions both by the stimulation of thyroid hormones and by its action on the lym-phoid cells (Berczi, 1997, 1994; Fabris et al., 1995).

The proopiomelanocortin derived peptides - ACTH, α-melanocyte stimulating hor-mone (α-MSH) and �-endorphin (�-END) - act antagonistically to GH and PRL and suppress adaptive immune responses by acting on the nervous, endocrine and immune systems (Berczi, 2001; Vamvakopoulos et al., 1994). It has been shown that α-MSH suppresses nuclear factor-κB (NF-κB) activated by various inflammatory agents and that this mechanism probably contributes to α-MSH induced anti-inflammatory effects (Manna and Aggarwal, 1998). The influence of ACTH on immune status is mediated mainly via glucocorticoids, released from the adrenal gland, which affect immune res-ponses via glucocorticoid receptors expressed by immune cells. Whereas it was initially thought that glucocorticoids mediate immunosuppression, more recent studies indica-te that they suppress Th1 and activate Th2 cytokines (Almawi et al., 1999). Thus, ACTH-induced changes of immune system activity are not always immunosuppressive, but rather immunomodulatory (Sternberg, 1997). It is necessary to take into consi-deration that immune cells also possess a capacity to produce some hormones, e.g. PRL, GH (Savino and Dardenne, 1995). Another humoral „effector“ of immunity is oxytocin, a hormone synthesized in the hypothalamus and secreted from the pituitary gland. Oxytocin has imunomodulatory roles (e.g., Yang et al., 1997) and is relevant to tumorigenesis since it may have a role in suppressing tumor cell proliferation (Cassoni et al., 2004).

Therefore, the interplay between hormones released from the CNS and immune cells might participate in the modulation of immune functions.

Neuronal pathwaysBoth the sympathetic and parasympathetic parts of the autonomic nervous sys-

tem may modulate immune processes in the organism. All lymphoid organs receive autonomic innervation and cells located in the lymphoid tissues possess receptors for transmitters released from autonomic nerves (Czura and Tracey, 2005; Dardenne and Savino, 1994; Elenkov et al., 2000).

The immune system is regulated, to a great extent, by the sympathetic nervous system (SNS), which innervates the majority of lymphoid organs (Basu and Dasgupta,

20 NEUROBIOLOGY OF SOMATIC DISEASES

20

Figure 2. Pathways, which transmit information from the brain to the immune system (A-E).(A) Hormones released from the pituitary gland (e.g. ACTH, prolactin, GH) might modulate immune function.(B) Acetylcholine released from postsganglionic vagal neurons (VNpo) bind to nicotine receptors of immune cells and produces an anti-inflammatory effect.(C, D) Norepinephrine released from postganglionic sympathetic neurons (SNpo) and epine-phrine/norepinephrine released from adrenal medulla might influence immune functions after binding to adrenergic receptors on the immune cells.

VNpo

SNpo

sympatheticnerves

ACTH

D

C

E

adrenalgland

SNpr

sympatheticganglion

A

BA

immunecell

VNpr

circulation

vaga

l sen

sory

gang

lion

vagalganglion

vagale�erents

213. Neuro-endocrine-immune interactions

2000; Weigent and Blalock, 1987, Denes et al., 2005). For example, the spleen has ex-clusively only sympathetic innervation (Stevens-Felten and Bellinger, 1997). It is well documented that catecholamines released from sympathetic nerve endings modulate the function of many components of the immune system via adrenergic and purinergic receptors on immune cells (Elenkov et al., 1995, 2000; Hasko and Szabo, 1998; Tracey, 2002; Vizi et al., 1995). Recent findings also show that the SNS is important in the regulation of the egress of hematopoietic cells from bone marrow (Katayama et al., 2006). Moreover, the SNS may modulate immune functions also by direct regulation of blood flow (Vizi, 1998). Experimental data show that interruption of the SNS in animals has produced enhancement or suppression of inflammation, depending on the stage of development at which the system is ablated, and whether the system is inter-rupted at a local or systemic level (Sternberg, 1997).

It is well established that afferent neural pathways in the vagus nerve participate in the brain-mediated responses to inflammation (Sternberg, 1997). In addition to this sensory function of the vagus nerve, an efferent or motor vagus nerve mechanism has also been described by which acetylcholine, the principal vagus nerve neurotrans-mitter, inhibits cytokine release from resident tissue macrophages (Borovikova et al., 2000b). The findings show that both pharmacological and electrical stimulation of the vagus nerve can attenuate the systemic inflammatory response via cholinergic anti--inflammatory pathways (Bernik et al., 2002).

It is necessary to point out that lymphocytes of the various immunological com-partments were found to be equipped with the key enzymes for the synthesis of both acetylcholine and catecholamines (Rinner et al., 1998; Kawashima and Fujii, 2003; Qiu et al., 2004). Therefore effect of acetylcholine and catecholamines released by immune cells in paracrine manner might co-operate/interfere with effect of neurotransmitters released by autonomic nerves within immunological compartments.

(E) Glucocorticoids released from adrenal cortex have complex effects on the immune system.The schema omits modulation of immune cells by somatic afferent sensory fibers that activated by inflammatory processes release neuropeptides via axonal reflex manner. Similarly, release of norepinephrine from sympathetic nerve ending might be modulated by cytokines released from neighboring immune cells (Straub et al., 1998). However, these mechanisms are primarily a con-sequence of local peripheral processes that are not initiated by activity of central nervous system.SNpr - preganglionic sympathetic neurons; VNpr - preganglionic vagal neurons.