Coordination of GCMediated Control of the Neuroimmune Response and Energy Homeostasis Control

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Both basal and stress-related homeostasis is centrally coordinated by the sympathoadrenomedullary system (SAS), and by the HPA axis. When homeostasis is disturbed or threatened by immune challenge or by some stressors both the SAS and HPA axis become centrally activated, resulting in increased release of catecholamines from the adrenal medulla and peripheral sympathetic terminals, and increased GCs release from the adrenal cortex (Elenkov et al., 2000). In the periphery, the HPA axis is functionally connected with the adrenal medulla by GCs produced in the adrenal cortex, which, via an intra-adrenal portal vascular system, gain access to the adrenal medulla, where they induce the enzyme phenylethanolamine-N-methyl-transferase, which controls the synthesis of adrenaline and noradrenalin (Wurtman, 2002). Additionally, both SAS and the HPA axis are centrally controlled by the PVN, which integrates humoral, visceral, sensorial, emotional, and cognitive information to operate, via neuroendocrine and pre-autonomic pathways, the coordinated control of basal energy and fluid homeostasis, as well as the immune, metabolic, physiological, and behavioral adaptations to different stressors (Swanson and Sawchenko, 1980; Yang et al., 1997). Preautonomic sympathetic neurons located in the

PVN send axons to relay centers in the brainstem, which give rise to preganglionic efferent fibers terminating in the spinal column ganglia. From these ganglia, postganglionic noradrenergic sympathetic fibers innervate virtually all systems, except the skeletal muscle, to ultimately stimulate the endocrine release of catecholamines from the adrenal medulla, and regulate the visceral function. The adrenal medulla has two separate populations of adrenaline-containing cells (A cells) and noradrenalin-containing cells (NA cells), which are innervated by separate groups of the preganglionic sympathetic neurons (Edwards et al., 1996; Yamaguchi-Shima et al., 2007). Most of the circulating adrenaline is secreted by adrenal A cells, while circulating noradrenalin seems to reflect the secretion from adrenal NA cells in addition to the release from sympathetic nerves (Edwards et al., 1996; Folkow and Von Euler, 1954; Vollmer et al, 1997; Wurtman, 2002). Circulating catecholamines and the noradrenalin locally released from sympathetic nonsynaptic varicosities into the lymphoid organs modulate the immune response by affecting lymphocyte traffic, circulation, and proliferation, and by modulating cytokine production (Elenkov et al., 2000). Circulating GCs and catecholamines are also critical for metabolic adjustments required during periods of fasting related to lack of food availability or due to the impossibility to search for food, ifthe animal is ill, or due to the impossibility of food digestion, in case of food poisoning or other causes for sickness. In such situations, metabolic energy stores, such as glycogen and fatty, must be mobilized as glucose and fatty acids in order to provide metabolic energy until the animal recovers conditions to acquire nutrients from the environment (Boyle et al., 1989; John et al., 1990; Peinado-Onsurbe et al., 1991).

When either the bee venom melittin, which stimulates AA release, or AA itself, is injected intracerebroventricularly (i.c.v.), they dose-dependently elevate plasma levels of both adrenaline and noradrenalin. The COX2 inhibitor indomethacin abolishes the responses to both melittin and AA, indicating that COX2 products mediate the activation of the SAS outflow in response to this central insult. More specifically, i.c.v. administration of PGE2, but not PGD2, PGF2a, or PGI2, significantly elevates plasma levels of noradrenalin, but not adrenaline. On the other hand, a thromboxane A2 mimetic microinjected into the PVN elevates plasma adrenaline, but has little effect on noradrenalin. Accordingly, inhibition of thromboxane A(2) synthase abolishes only the elevation of adrenaline, but not of noradrenalin, induced by either i.c.v. melittin or AA (Yokotani et al., 2000). Several signaling factors that stimulate SAS outflow via prostanoids are also involved in the central suppression of appetite in response to stress and/or sickness. For instance, i.c.v. injection of the neuropeptides urocor-tin, CRH, or glucagon-like peptide-1 (GLP-1) causes COX2-dependent peripheral release of both catecholamines (Arai et al., 2008; Murakami et al., 2002). In all these cases, the release of adrenalin also proved to be mediated by thromboxane A2 (Arai et al., 2008; Yokotani et al., 2001). Both uro-cortin and CRH suppress appetite and stimulate SAS by activating the same CRH1 receptor in the PVN (Yokotani et al., 2001). Likewise, when synaptically released onto the PVN, GLP-1 activates CRH-expressing neurons, leading downstream to CRH-mediated suppression of food intake (Rowland et al., 1997; Turton et al., 1996). Centrally administered IL-1b also causes COX-dependent stimulation of the SAS- and CRH-dependent appetite suppression (Callahan and Piekut, 1997; Luheshi et al., 1999; Mrosovsky et al., 1989; Uehara et al., 1989; Yokotani et al., 1995). Receptors located in the PVN are also involved in the central anorexigenic effect ofhistamine and bombesin-like peptides, which also induces COX-dependent elevation of circulating catecholamines (Arora and Anubhuti, 2006; Ookuma et al., 1989; Sakata et al., 1997; Shimizu et al., 2005, 2007).

The central stimulation of SAS outflow by vasopressin, histamine, bombesin, or CRH were not affected by PLA2 inhibitors, but were dose-dependently reduced by inhibitors of PI-PLC and DAG lipase blockers (Okada et al., 2002, 2003; Shimizu et al., 2004). Furthermore, vasopressin effect was attenuated by a MAG lipase inhibitor. Together these results indicate that 2-AG could provide some of the neuropeptide-induced AA necessary for COX2-dependent SAS activation (Shimizu and Yokotani, 2008). In fact, central administration of 2-AG itself caused MAG lipase-dependent increase in circulating catecholamines (Shimizu and Yokotani, 2008). On the other hand, central cannabinoid CB1 receptor activation by a synthetic cannabinoid (WIN 55212-2) dose-dependently reduced the vasopressin-induced response, whereas the CB1 antagonist AM251 led to the opposite effect (Shimizu and Yokotani, 2008). These results indicate that the endogenous hypothalamic 2-AG (and perhaps AEA) is likely to suppress SAS outflow by acting at CB1 receptor. However, once metabolized by MAG lipase, 2-AG provides AA for COX2-mediated synthesis of prostanoids that, in turn, activate SAS outflow. It is also possible that COX2-mediated formation of PGE2-G will activate preautonomic neurons, leading to SAS activation. On the other hand, since GCs cause the release of 2-AG in the PVN (Malcher-Lopes et al., 2006), it seems very likely that GC-induced endocannabinoids may reduce synaptic activation of the SAS outflow in the same way as they do for the PVN neuroendocrine cells.

Both GCs (Tempel et al., 1993) and the cannabis-derived cannabinoid THC (Verty et al., 2005) cause increased appetite and weight gain when injected directly into the PVN. In fact, the PVN is the only hypothalamic center in which local GC application leads to hyperphagia (Tempel et al., 1993). The fact that endocannabinoids mediate the inhibitory effects of GCs in the PVN, along with several indirect evidences, indicates that the orexigenic effect of GCs are mediated, at least in part, by endocannabinoids via cannabinoid CB1 receptor activation in the PVN, which also contributes to explain the orexigenic effect of marijuana (Di et al., 2003;

Malcher-Lopes et al., 2006). On the other hand, GC-induced biosynthesis of both 2-AG and AEA in the PVN is completely blocked by leptin (Malcher-Lopes et al., 2006), which is an anorexigenic cytokine-like peptide produced by the adipose tissue, functioning as a major peripheral signal informing the CNS about the current nutritional state (Ahima, 2000; Ahima and Osei, 2004; Ahima et al., 1996). Leptin was also shown to prevent fasting-induced hyperphagia by blocking fasting-induced biosynthesis of endocannabinoids in the hypothalamus (Di Marzo et al., 2001; Kirkham et al., 2002). There are evidences that leptin-promoted short-term suppression of appetite and meal termination involves the activation of preautonomic oxytocinergic PVN neurons (Blevins Leptin can also stimulate SAS outflow when injected i.c.v.; however, the primary hypothalamic site for this action seems to be the ventromedial hypothalamus, not the PVN (Satoh et al., 1999).

Leptin is released by adipose tissue in response to AA or PGE2, and circulating leptin is involved as a mediator for the LPS-induced anorexia and fever in rats (Fain et al., 2001; Sachot et al., 2004), which supports a key role of this peptide in the peripheral coordination between energy homeo-stasis and the adaptation to stress and inflammation. Additionally, in the CNS, this peptide acts as an indirect inflammatory signal by causing IL-1b release from microglial cells, by inducing IL-1b expression in macrophages located in the meninges and perivascular space, and by inducing COX2 expression in endothelial cells (Inoue et al., 2006; Pinteaux et al., 2007). Moreover, leptin has been shown to stimulate cPLA2 activity in bone marrow stromal cells, in alveolar macrophages and in muscle cells, leading, in the later two cases, to increased AA release (Bendinelli et al., 2005; Kim et al., 2003; Mancuso et al., 2004). Accordingly, leptin was shown to cause the release of PGE2 and PGF2a in the neonatal hypothalamus (Brunetti et al., 1999). Hence, acting as a proinflammatory factor, leptin may promote a shift toward AA mobilization and, perhaps, AA-containing endocannabi-noid metabolism by COX2, favoring prostanoids production in the endo-thelial cells and in the hypothalamic cells under the influence of IL-1b secreted by glial cells and macrophages. As a nutritional state-dependent modulator of energy homeostasis, leptin acts in the PVN to suppress GC-induced release ofendocannabinoids and in the ventromedial hypothalamus to prevent activity-dependent release of endocannabinoids (Jo et al., 2005; Malcher-Lopes et al., 2006). In all these cases, leptin actions tend toward the prevention ofendocannabinoid accumulation. Additionally, leptin has been shown to stimulate the expression and the activity ofFAAH in lymphocytes (Maccarrone et al., 2003), and, in the uterus of leptin knockout (ob/ob) mice, levels of both AEA and 2-AG are significantly elevated as compared to wild-type littermates, due to reduced activity of both FAAH and MAG lipase (Maccarrone et al., 2005). There are indications, however, that leptin stimulatory effect on FAAH may not occur in hypothalamic neurons, since it was absent in neuroblastoma cells (Gasperi et al., 2005), and FAAH activity was not increased in leptin treated rat hypothalamus as accessed by postmortem assays with tissue extracts (Di Marzo et al., 2001). Nevertheless, it is still an open question whether or not leptin modulates MAG activity in the CNS.

The cytokine IL-1b is released in the brain by glial cells (Griffin et al., 1995) and by activated macrophages in the periphery, functioning as a major mediator of the humoral communication between the peripheral immune system and the CNS. IL-1b is transported from blood to brain across the blood-brain barrier by a saturable system (Banks et al., 1989; Coceani et al., 1988; McLay et al., 2000). IL-1b has been shown to activate the HPA axis, however, the receptors for IL-1b (IL-1R) do not seem to be localized on PVN neurons, leading to the assumption that it may act through IL-1R receptors located on endothelial cells, which are abundant on PVN blood vessels, to stimulate local release of prostaglandins (Parsadaniantz et al., 2000; Quan et al., 2003). Prostaglandin in turn stimulates the HPA axis and other neuroendocrine systems (Berkenbosch et al., 1987; Besedovsky et al., 1986; Del Rey et al., 1987; Sapolsky et al., 1987). In respect to IL-1b role in the coordination between energy homeostasis and immune response, it is striking that, besides being stimulated by the anorexigenic hormone leptin, IL-1b itself stimulates neuronal activity to induce anorexia and loss of body weight when injected into the PVN (Avitsur et al., 1997). Electrophysiological studies showed that IL-1b inhibits local GABA synaptic inputs into both parvocellular and magnocellular PVN neurons, thereby disinhibiting them and facilitating their depolarization (Ferri and Ferguson, 2003; Ferri et al., 2005), an effect that was abolished by COX inhibitors, indicating the participation of prostaglandins as downstream mediators of IL-1b synaptic effects. Furthermore, both IL-1b and PGE2 also caused hyperpolarization (inhibition) in putative GABAergic hypothalamic neurons surrounding the PVN (Ferri and Ferguson, 2005), which are probably inhibitory interneur-ons upstream from the PVN neuroendocrine cells (Boudaba et al., 1996). In fact, COX inhibition abolished the activation of the HPA axis by both central and peripheral administration of IL-1b (Katsuura et al., 1988; Parsadaniantz et al., 2000). COX inhibitors also blocked IL-1-, IL-2-, and IL-6-induced CRH release from medial basal hypothalamic explants (Karanth et al., 1995; Navarra et al., 1991).

Therefore, it seems that the integrative role of the hypothalamus, especially of the PVN, in coordinating metabolic, physiological, and behavioral adaptations to different stressors strongly relies on a regulatory switch centered at the GC-dependent determination of the AA metabolic fate in a nutritional and inflammatory state-dependent fashion, as signaled by hypothalamic levels of leptin and IL-1ß. Thus, low levels of leptin and/or IL-1b are permissive for the GC-induced production of AA-containing endocannabinoids in the hypothalamus. In the PVN, the subsequent CB1

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