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Neuroendocrine mechanisms for immune system regulation during stress in fish
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Fish & Shellfish Immunology journal homepage: www.elsevier.com/locate/fsi
Neuroendocrine mechanisms for immune system regulation during stress in fish Q4
s a, Mo nica Imarai b, Gino Nardocci a, Cristina Navarro a, Paula P. Corte ~ a-Castillo b, **, Margarita Montoya b, Beatriz Valenzuela b, Pablo Jara b, Claudio Acun a , * ndez Ricardo Ferna gicas y Facultad de Medicina, Universidad Andr Facultad de Ciencias Biolo es Bello, Santiago, Chile. Av. República 252, 8370134 Santiago, Chile Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile. Av. Libertador Bernardo n Central, 9170022 Santiago, Chile O'Higgins 3363, Estacio
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Article history: Received 19 February 2014 Received in revised form 10 July 2014 Accepted 3 August 2014 Available online xxx
In the last years, the aquaculture crops have experienced an explosive and intensive growth, because of the high demand for protein. This growth has increased fish susceptibility to diseases and subsequent death. The constant biotic and abiotic changes experienced by fish species in culture are challenges that induce physiological, endocrine and immunological responses. These changes mitigate stress effects at the cellular level to maintain homeostasis. The effects of stress on the immune system have been studied for many years. While acute stress can have beneficial effects, chronic stress inhibits the immune response in mammals and teleost fish. In response to stress, a signaling cascade is triggered by the activation of neural circuits in the central nervous system because the hypothalamus is the central modulator of stress. This leads to the production of catecholamines, corticosteroid-releasing hormone, adrenocorticotropic hormone and glucocorticoids, which are the essential neuroendocrine mediators for this activation. Because stress situations are energetically demanding, the neuroendocrine signals are involved in metabolic support and will suppress the “less important” immune function. Understanding the cellular mechanisms of the neuroendocrine regulation of immunity in fish will allow the development of new pharmaceutical strategies and therapeutics for the prevention and treatment of diseases triggered by stress at all stages of fish cultures for commercial production. © 2014 Published by Elsevier Ltd.
Keywords: Fish Neuroendocrine Immunology Stress Chromaffin cells Hypothalamus-pituitary-interrenal axis
1. Introduction The growing global demand for protein has led to the development of intensive aquaculture crops. However, the explosive growth experienced by this sector has been limited by a number of factors that have increased fish susceptibility to fatal diseases. It has been established that the constant biotic and abiotic changes that occur in cultured species induce physiological, endocrine and immunological responses in fish. These responses
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* Corresponding author. Laboratorio de Fisiología, Departmento de Ciencias gicas, Facultad de Ciencias Biolo gicas y Facultad de Medicina, Universidad Biolo s Bello, Av. República 252, 8370134 Santiago, Chile. Tel.: þ56 226615650. Andre ** Corresponding author. Laboratorio de Inmunoterapia, Centro de Biotecnología Acuícola, Universidad de Santiago de Chile, Av. Libertador Bernardo O'Higgins 3363, n Central, 9170022 Santiago, Chile. Tel.: þ56 227181169. Estacio ~ a-Castillo), rhfdez@gmail. E-mail addresses: [email protected] (C. Acun com, [email protected] (R. Fern andez).
help to mitigate the effects at the cellular level and maintain the internal environment (homeostasis). Different processes participate in preserving the physiological balance or allostasis. These process integrate autonomic, neuroendocrine, metabolic and behavioral components [1]. When an adequate adaptation response fails, the individuals generate an allostatic overload that produces pathological conditions [2]. The response to stimuli that generate an imbalance in the allostasis of an organism is known as stress, and the stimuli that generate it are called stressors [3]. For many decades, we have studied the effects of stress on the immune system in animal models [4]. While acute stress can have beneficial effects, chronic stress inhibits immune responses in both mammals and teleost fish [5e8]. Examples of stressors include physical (i.e., noise, vibration, pain, shock, temperature), psychological (i.e., exposure to a new or uncontrolled environment) and social (i.e., space availability). There are also stressors generated in the body that involve the cardiovascular system and metabolic homeostasis (i.e., hemorrhage,
http://dx.doi.org/10.1016/j.fsi.2014.08.001 1050-4648/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Nardocci G, et al., Neuroendocrine mechanisms for immune system regulation during stress in fish, Fish & Shellfish Immunology (2014), http://dx.doi.org/10.1016/j.fsi.2014.08.001
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exercise, heat exposure) [9]. Despite of this, individuals have general mechanisms in response to stress (Fig. 1), which involve a signaling cascade triggered by the activation of neural circuits in the central nervous system (CNS), such as cortical, limbic and hypothalamic structures (primary response [10]). In this response, the hypothalamus is the central modulator of stress, and catecholamines, corticosteroid-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and glucocorticoids are essential neuroendocrine mediators for this activation [11,12]. Whether stress is prolonged in time, the activated pathways evoke alterations in metabolic and cellular functions, osmoregulatory disturbances, and changes in the immune function (secondary response). Specifically in fish, the dynamic equilibrium is constantly threatened by intrinsic and extrinsic stressors. For example, high densities, non-natural habitats and unusual “social situations”, such as the frequent handling (e.g., during vaccination procedures), transport, overeating and sub-optimal water quality (e.g., variable temperatures, waste products, chemicals environmental pollutants), may generate an allostatic overload that affects the normal behavior and physiology in susceptible individuals. All the stressors may trigger a chronic stress in these individuals and may cause an anorexia state, alterations in locomotor patterns, and increases in the cortisol levels in the plasma and the serotonin levels in the brain [13,14]. These responses may trigger a delay in growth and a consequent reduction in the size of the fish, which would eventually lead to lower protein content. These later changes in the whole animal are known as tertiary response. The stressors trigger a series of regulatory events that interfere with the normal function of the immune system [15,16] and facilitate a rapid pathogenic expansion. To prevent and effectively treat infectious diseases, it is necessary to understand the elaborate bidirectional communication between the neuroendocrine system and the immune system. This communication is required to address damage or injury. A well-regulated inflammatory response is essential for overcoming an infection. However, an excessive inflammatory response can cause the destruction of tissue. The mechanisms that trigger stress (e.g., exposure to a pathogen) induce energy redistribution as a result of the sustained increases of hormonal activity (e.g., cortisol). The increased hormonal activity causes suppression of the functions (i.e., immune system) that are “less important” when survival is at risk [17]. Despite of this, exist immunosuppressive mechanisms that can protect the host cells against the extensive action of the immune response [18].
Fig. 1. Perceived stressors act on fish central nervous system to evoke primary (acute), secondary (transition) and tertiary (whole animal, chronic) physiological and related effects.
2. Reflex control of inflammation in mammals: neuroendocrine-to-immune communication The stress response in mammals is an integrated physiological and psychological reaction, and neuroendocrine responses are key to overcoming adversity. Increasing evidence supports the hypothesis that “healthy organs behave as ‘biological oscillators', which couple to one another, and this orderly coupling is maintained through a communication network, including neural, humoral, and cytokine components” [19]. This coupling is established through shared receptors and signal molecules to ensure physiological homeostasis and survival. The best-studied example of immune-neuroendocrine communication in mammals is the interaction between the components of the hypothalamus-pituitary-adrenal (HPA) axis (Fig. 2A). This axis is driven by a neural signal originating in the paraventricular nucleus (PVN) [20] and the immune system. Both endotoxin (i.e., lipopolysaccharide, a component of Gram-negative bacteria) and cytokines stimulate HPA anti-inflammatory responses by the production of adrenal glucocorticoids [12] or by inhibiting prolactin secretion. Prolactin is a potent regulator of humoral and cellular immune responses during physiological and pathological states [21]. Thus, the HPA- or ‘stress-axis’ conveys stress stimuli from the brain to the periphery. A stress stimulus also increases sympathetic activity [22]. Evidence accumulated over the last 30 years suggests that norepinephrine (NE), which is the main neurotransmitter of the sympathetic nervous system, fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs in the following ways: i) primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervations; ii) upon stimulation, NE is released from the sympathetic nerve terminals in these organs; and iii) the target immune cells, such as lymphocytes and macrophages, express adrenergic receptors (AR, adrenoceptors) [23,24]. Adrenoceptors are G-protein coupled receptors. Adrenoceptors can be divided into a- and b-AR subgroups, which can be further subdivided into different subtypes. Neutrophils, mononuclear cells, natural killer cells and T- and B-lymphocytes express a- and b-AR.
Fig. 2. Schematic representation of (A) the hypothalamus-pituitary-adrenal (HPA) axis in mammals; and (B) the hypothalamus-pituitary-interrenal (HPI) axis in fish. CRH, corticosteroid-releasing hormone; ACTH, adrenocorticotropic hormone.
Please cite this article in press as: Nardocci G, et al., Neuroendocrine mechanisms for immune system regulation during stress in fish, Fish & Shellfish Immunology (2014), http://dx.doi.org/10.1016/j.fsi.2014.08.001
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However, b2-AR is the most important adrenoceptor with respect to the immune system. b2-AR activation increases cAMP concentrations, which can modulate cytokine expression by decreasing tumor necrosis factor (TNF)-a and increasing interleukin (IL)-8 [25]. Conversely, a2A-AR stimulation increases TNF-a gene expression in Kupffer cells and plasma TNF-a during sepsis [26]. Thus, AR stimulation through locally released NE or circulating catecholamines affects lymphocyte trafficking, circulation, and proliferation and modulates cytokine production and the functional activity of different lymphoid cells [23]. The CNS can also rapidly inhibit the release of macrophage TNFa and attenuate systemic inflammation responses acting through the vagus (parasympathetic) nerve. This physiological mechanism is termed the ‘cholinergic anti-inflammatory pathway’ [27]. In human macrophages cultured in vitro acetylcholine (ACh), the main vagal neurotransmitter inhibits LPS-induced the release of proinflammatory cytokines TNF-a, IL-1b and IL-6, but not increases the anti-inflammatory cytokine IL-10 [27,28]. In addition, vagus nerve electrical stimulation inhibits TNF-a production and prevents the development of shock in rats [27]. Recent work on the anatomical basis of the cholinergic antiinflammatory pathway indicates that the spleen is required for vagus nerve control of inflammation [29]. In splenectomized rats injected with endotoxin, the level of serum TNF-a is reduced by 70% and vagus nerve stimulation fails to further suppress TNF-a [30]. The spleen is innervated by the splenic nerve that originates in the celiac-superior mesenteric plexus, and the celiac branches of the vagus terminate at that location [31]. The splenic nerve is composed mainly of catecholaminergic fibers that terminate in close apposition to immune cells [32]. Thus, the effects of TNF-a production induced by vagus nerve stimulation are mediated by NE released from splenic nerve endings. These data confirm the importance of the adrenergic transmitters in the regulation of immune responses [24,33]. 3. Neuroendocrine and immune responses to stress in fish Teleost fish are amongst the oldest vertebrates and have an immune system similar to that of mammals. They have an innate defense and aspects of the adaptive immune system. As in mammals, teleost fish possess lymphoid organs, such as the thymus, spleen and kidney [34]. However, unlike higher vertebrates, fish do not have bone marrow or a lymphatic system [35]. Fish have a cellecell contact communication system, including soluble mediators such as cytokines, to direct the immune response and communicate the recognition of stressors (e.g., pathogens) and regulate the magnitude of the response. Moreover, the immune system acts as a sensor [36] that informs the CNS to trigger a neuroendocrine response. Thus, stress leads to neuroendocrine communication between the CNS, the autonomic nervous system and the hypothalamus-pituitary-interrenal (HPI) axis (Fig. 2B). These systems regulate the immune system and decrease immune function in fish when it is hyperactive [6]. This means that neuroendocrine system signals affect normal immune system function [37]. Teleost fish have developed an effective immune system. The first barrier that a pathogen must defeat is a biochemical barrier that prevents their invasion. The barrier consists of an integumental mucosa layer with antibacterial peptides such as lysozyme, lectins and proteases [38]. If the pathogens cross this biochemical barrier, there is an additional mechanism of defense composed of phagocytic cells similar to those found in mammals. These cells include macrophages, neutrophils and natural killer cells in addition to B- and T-lymphocytes [39,40]. It has been reported that a variety of these immunocompetent cells possess the
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molecular machinery to respond to neuroendocrine factors because they have receptors for neurotransmitters, neuropeptides and hormones [41,42]. Moreover, it has also been demonstrated that leukocytes synthesize neuroendocrine mediators [43]. The data indicate the presence of receptors and hormones in immune cells. Additionally, the receptors for the soluble mediators are present in the neuroendocrine system, and there is a relationship between immunostimulation and immunosuppression against stress. 3.1. The hypothalamus-pituitary-interrenal (HPI) axis Immune-endocrine interactions in fish and the central role of the HPI axis are well summarized elsewhere [44]. Briefly, when teleost fish are exposed to a stressor, the structure that acts as an intermediary between the neuroendocrine pathway and the immune system is the head kidney. The head kidney possesses both endocrine and immune functions. The chromaffin cells of the head kidney are located in the walls of the posterior cardinal vein. These cells produce catecholamines, whereas the interrenal cells produce cortisol. Thus, the head kidney is the functional analog of the mammalian adrenal gland [45]. Both lymphoid (B- and T-lymphocytes) and myeloid (phagocytic) cells are produced in the head kidney hematopoietic tissue, which makes it the functional analog of the mammalian bone marrow [35]. This organization facilitates a direct paracrine interaction between the hematopoietic and endocrine tissues in the head kidney [42,46]. The anatomical organization of the head kidney suggests that the mediators secreted by the brain-(para)sympathetic-chromaffin cell axis, such as epinephrine and NE, and cortisol secreted by the HPI establish a direct paracrine communication between the immune system cells and vice versa. Cortisol is the main hormone produced by the stimulation of the interrenal gland (in a similar manner to the stimulation of the adrenal cortex in humans) [47]. When stress signals are perceived, the hypothalamic region of the nucleus pre-opticus of the brain responds by releasing CRH into the pituitary. This signal is received by the CRH receptor subtype 1 (CRH-R1) on pituitary corticotropes from the pars distalis. The binding of CRH with its receptor stimulates ACTH release into the circulation [48,49]. Subsequently, ACTH stimulates the production and release of the main corticosteroid cortisol by interrenal cells of the head kidney. Cortisol exerts its effect on target cells by binding to the cytosolic glucocorticoid receptor (GR) [50]. The cortisol-GR complex translocates into the nucleus, where it binds to glucocorticoid responsive elements (GRE) and modifies gene expression [51]. As in mammals, both the GR and the mineralocorticoid receptor are capable of binding cortisol [52]. In contrast to mammals, fish have duplicate GR genes (GR1 and GR2) that are translated into functional proteins [51]. GR1 also exists in two alternative splice variants (GR1a and GR1b) [53,54]. Thus, there are four receptors capable of binding cortisol in fish: GR1a, GR1b, GR2, and MR. However, their ability to induce activation of downstream genes is dependent on the cortisol concentration [55]. Corticosteroids regulate multiple aspects of immune defenses in mammals and influence the secretion of pro- and antiinflammatory cytokines [4]. Similarly, cortisol receptors have been described in fish immune cells, and cortisol affects the immune response in common carp (Cyprinus carpio) [54,55], rainbow trout (Oncorhynchus kisutch), and gilthead sea bream (Sparus aurata) [56]. Cortisol acts through the GR to regulate differential and profound effects on the immune system in teleost fish. Several in vitro studies have shown that cortisol inhibits LPS-induced expression of acute phase protein serum amyloid S (SAA) and pro-inflammatory
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cytokines such as IL-1b, TNF-a, IL-12, and iNOS activity [6,48,57]. The expression of cytokines is important, because can affect the activity of the HPI axis [58] principally in acute stress. Studies of the innate immune response in vitro have shown that cortisol decreases the phagocytosis of head kidney cells from tilapia, common carp and silver sea bream (Sparus sarba) [59]. Cortisol also inhibited chemotaxis and phagocytosis in a goldfish macrophage cell line and strongly inhibited respiratory burst activity in a dose-dependent matter [60]. In agreement with these results, cortisol also inhibits the pro-oxidative activity of leukocytes from head kidney in golden sea bream [61]. Cortisol also inhibited the proliferation of a monocyte/macrophage cell line from rainbow trout [62] and induced programmed cell death (apoptosis) of macrophages from silver sea bream and Atlantic salmon (Salmo salar) [6]. These in vitro results have been confirmed by in situ experiments [15]. In S. salar, the immunosuppression mediated by the chronic administration of cortisol (simulating chronic stress) decreased the relative expression of Interferon (IFN) a-1, Heatshock proteins 70 (HSP70) and 90 (HSP90), SAA, and GR. These changes were accompanied by a higher prevalence of pathogens such as the infectious pancreatic necrosis virus (IPNV) [63]. Studies of the adaptive response in vitro have shown that cortisol reduces immunoglobulin (Ig) M secretion by lymphocytes isolated from the spleen, head kidney and blood from common carp [64]. Furthermore, in situ temperature stress decreases the antibody responses after immunization [46]. In addition, cortisol inhibits the proliferation and induces apoptosis of lymphocytes from the blood, head kidney, spleen and thymus [65]. This process is dependent on GR, and RU486 (mifepristone), a specific GR blocker, prevents these processes [66]. Stress-induced immunosuppression could be controlled based on knowledge of the interaction between the neuroendocrine and immune systems. In particular, the HPI axis may be altered at different levels to suppress the production or the effect of cortisol under stress conditions. Modulation is based in the established hierarchical control of the axis, where CRH plays a key role in the systemic response to stress by modulating corticotropes activity and ACTH production [67]. The main function of ACTH in fish is the regulation of the steroidogenesis of cortisol in the interrenal cells of the head kidney [17] as ACTH is the main stimulus for production [67]. In rainbow trout, the use of mifepristone decreases stressinduced cortisol secretion by reducing hypothalamic CRH mRNA expression [68]. Furthermore, the sympatho-adrenergic stimulation causes cortisol release during confinement [69]. The corticotropic action of CRH can be avoided by the administration of the non-selective antagonist of the CRH receptor, the CRF(9e41) a-helix [70]. Another hypothalamic factor is melaninconcentrating hormone (MCH). MCH is a strong inhibitor of basal and CRH-stimulated ACTH secretion [71,72]. In addition, rainbow trout acclimated to an environment with abundant light have higher circulating levels of MCH and ACTH in plasma and lower cortisol than fish acclimated to a dark environment [73,74]. MCH is a heptadecapeptide that mediates color changes in teleost fish (antagonist of the alpha melanocyte stimulating hormone a-MSH) [75], and its plasma levels are modified during stress conditions. In 1996, an orexigenic role for hypothalamic MCH in the regulation of food intake and energy balance in mammals was demonstrated [76]. The exogenous administration of either barfin flounder (Verasper moseri) or human MCH in goldfish produces an anorexigenic effect [77]. However, this anorexigenic effect is significantly lower than the effect of CRH on food intake and energy balance in fish during stress conditions. The anorexigenic effect of CRH during stress may be prevented by the action of CRF(9e41) a-helix or MCH if administered either directly or induced by changes in the fish photoperiod.
3.2. The autonomic nervous system In mammals, lymphoid organs are innervated by both sympathetic and parasympathetic nerve fibers [23,78,79], whose activation stimulate or inhibit the immune response. Furthermore, we also know that leukocytes express both cholinergic and adrenergic receptors [80]. However, little is known about the cholinergic system in fish. Our understanding of the cholinergic system in fish is less than our understanding of the adrenergic system, which is predominant in response to stress. Because catecholamine receptors of the sympathoadrenomedullary system are present on immune cells of teleost fish [81], it is possible to hypothesize a direct autonomic innervation of the fish immune system. In fact, many lymphoid tissues receive sympathetic innervation. For example, in coho or silver salmon (O. kisutch), the spleen is highly innervated by adrenergic fibers in the vasculature and parenchyma [82]. Several radioligand binding experiments have demonstrated the presence of b-ARs in the anterior kidney, spleen and peritoneal leukocytes of goldfish (Carassius auratus) [83]. b-ARs have also been found in membranes isolated from the head kidney and from spleen leukocytes of the American catfish (Ictalurus punctatus) [84]. These results are complemented with the sequencing and characterization of a1-AR in teleosts and facilitate the functional studies of the immune system and other tissues [85,86]. Considering the mediators involved in the functional interactions, the direct influence of sympathetic innervations on the immune system of teleost fish is exerted through of the binding of epinephrine and NE to their functional adrenoceptors, a-AR and bAR that are present in the cells of the immune system [81]. Catecholamines inhibit the innate and acquired immune response in various species of teleosts through the activation of b-AR. However, a-AR stimulation leads to the production of antibodies [81,87e89]. In tilapia (Oreochromis aureus), Chen and collaborators showed that catecholamines and cortisol induced by cold stress inhibit the phagocytic activity of leukocytes and decrease plasma levels of immunoglobulin M (IgM). Moreover, the combination of cortisol and isoproterenol (a non-selective b-AR agonist) have an additive effect in reducing phagocytosis in vitro [90]. In common carp (C. carpio), it was observed that the co-administration of adrenaline and zymosan A (an inductor of inflammation) reduced the percentage of monocytes/macrophages. Additionally, these treatments reduced the expression of CXCL8_L1 chemokine (a functional homolog of mammalian IL-8) and its receptors (CXCR1 and CXCR2), which influence leukocyte recruitment after stress [91]. Recently, Chadzinka et al. (2012) reported the sequence of b2aAR in common carp. b2a-AR mRNA is constitutively expressed in the brain, especially in the preoptic nucleus (homologous to the mammalian hypothalamus) and in immune organs. During the in vivo inflammatory response, b2a-AR expression was upregulated in the peritoneal leukocytes. Additionally, epinephrine inhibits the expression of pro-inflammatory cytokines, chemokines and their receptors in fish phagocytes cultured in vitro [42]. Finally, epinephrine may influence the inflammatory response via direct regulation of leukocyte migration and/or apoptosis during zymosan-induced peritoneal inflammation in common carp [91]. ~ a-Castillo Similar to mammals (reviewed by Fernandez & Acun in 2012 [24]), autonomic responses in fish can be influenced by the immune system through the cytokines produced by glial cells (e.g., astrocytes) in the CNS, which modulates neuroendocrine responses. The autonomic response can also be altered by peripheral signals that gain access to the CNS through the circumventricular organs, which are structures without bloodebrain barriers [92]. Conversely, catecholamine secretion from teleost chromaffin cells is regulated by a host of cholinergic and non-cholinergic pathways
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that ensure sufficient redundancy and flexibility in the secretion process to permit synchronized responses to a myriad of stressors [93]. 3.3. Other neuroendocrine-immune response modulators during stress It has been reported that other hormones participating in the hypothalamicepituitary axis are expressed in the cells of the fish immune system. These hormones include CRH [94], growth hormone (GH) and prolactin [95,96], in addition to the proopiomelanocortin (POMC)-derived peptides ACTH, b-endorphin and a-MSH [97]. Other hormones such as leptin I and leptin II were also found [48]. Interestingly, ACTH and ACTH receptor-like molecules are present during early development in immune tissues such as the thymus, spleen and the interrenal tissue [98]. ACTH has been implicated in increased oxidative burst activity in phagocytes [99]. CRH also induces a-MSH release from the pituitary. Both ACTH and a-MSH have been shown to have immunomodulatory effects. In thymic areas, POMC-derived peptides and cytokines colocalize with apoptotic cells and have a putative role in the selection and apoptosis of thymic lymphocytes [97]. In mammals, opiate alkaloids and endogenous opioid peptides exert their physiological and pharmacological actions through the following opioid receptors: the morphine-like receptor, mu (MOR, m, oprm), a delta receptor (DOR, d, oprd) and a kappa receptor (KOR, k, oprk). These receptors are expressed both on neuroendocrine cells and on leukocytes [100]. Opioids modulate both innate and acquired immune response. In fish, morphine administration affects nitric oxide production, chemotaxis and apoptosis of head kidney leukocytes from common carp cultured in vitro [101]. Additionally, in vivo experiments have shown that specific agonists of opioid receptors impair leukocyte migratory properties and cause reduced chemotaxis and reduced expression of chemokine receptors [102]. Opioids affect the activity of leukocytes and expression of inflammatory molecules both in vivo and in vitro by altering chemokines and chemokine receptors [103]. As in mammals, thyroid function in teleosts also affects the immune system. Early studies showed a decrease in the number of
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circulating leukocytes in hypothyroid fish, which could be restored by addition of thyroxin and human thyroid-stimulating hormone (TSH) [104]. Finally, sex steroids also could affect fish immunity. The androgen receptor is detected in salmonid lymphocytes and estrogen receptor-a is present in catfish leukocytes [105]. In acidophilic granulocytes from gilthead sea bream, which are the functional equivalent of mammalian neutrophils, estrogen signaling through the G protein coupled estrogen receptor (GPER) regulates granulocyte activation. GPER activation of acidophilic granulocytes in vitro reduces the respiratory burst and drastically alters the expression profile of several genes encoding major proand anti-inflammatory mediators. In addition, GPER signaling in vivo modulates adaptive immunity [106]. 4. Concluding remarks The explosive growth experienced by the fish-derived food sector has been limited by a number of factors that have increased the susceptibility of fish to diseases and death. Constant changes, including both biotic and abiotic alterations, affect species in culture and induce physiological, endocrine and immunological responses to mitigate those effects. To meet the increasing demand for animal proteins, aquaculture continuously requires new techniques to increase their production. The intensification of aquaculture practices has increased the levels of stress in the animals. Although fish possess well-developed immune and neuroendocrine systems, extensive research is needed to support the hypothesis that teleosts have evolved complex communication networks between healthy organs and systems that connect neural, humoral and cytokine components to achieve homeostasis. Therefore, the interactions among these systems are of special clinical and commercial interest. The activity of a single pathophysiological response in several disorders can lead to the suppression of opposite responses. This shows that when a condition activating one of these components occurs in response to stress, a variety of adaptive processes can lead to pathologic processes in the individual. When the stressor is acute and a short-term response is stimulated, the immune response of fish is to enhance innate function. Acute stress results in an increase in circulating leukocyte numbers.
Fig. 3. The effect of acute and chronic stress upon the immune system function.
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This phenomenon is related to the activation of the sympathetic nervous system and release of catecholamines, which mobilize both erythrocytes and leukocytes. If the stressor is chronic, the immune response is suppressed, and this increases the possibility of infection. It is believed that the harmful effects of stress on the immune response are preferentially mediated by the suppressive effects of glucocorticoids (i.e., cortisol) and are a consequence of the inability to adapt to chronic stressors. This may occur because coping with the stressor imposes an allostatic cost that may interfere with the required immune response (Fig. 3). Because the stress situations are energetically demanding, it is expected that other hormones involved in metabolic support will have an influence on immune function. As a result, GH, opioids and thyroid hormones also affect immune responses. It must be emphasized that unlike mammals, fish use a single organ called the head kidney as the primary site of cortisol (interrenal cells) and catecholamine (chromaffin cells) production in addition to hematopoiesis and antibody production. Thus, the direct paracrine interactions between the immune and neuroendocrine systems in this organ are critical. Understanding the cellular mechanisms of the neuroendocrine regulation of the immune response in fish will allow the development of new pharmaceutical strategies and therapeutics for the prevention and treatment of diseases triggered by stress at all stages of fish cultures for commercial production. Acknowledgments R. Fernandez is funded by FONDECYT 1120976 and UNAB DI~ a-Castillo, M. 354-13/R; G. Nardocci, by FONDECYT 3140414; C. Acun Imarai, M. Montoya, B. Valenzuela and P. Jara, by Consorcio de ~ a-Castillo is also Sanidad Acuícola CORFO 13CTE-21527; C. Acun funded by FONDECYT 1110734 and CORFO 13IDL1-18500; M. Montoya, by FIA PYT 2012-0023. References [1] McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav 2003;43:2e15. [2] McEwen BS, Gianaros PJ. Stress- and allostasis-induced brain plasticity. Annu Rev Med 2011;62:431e45. [3] McEwen BS, Wingfield JC. What is in a name? Integrating homeostasis, allostasis and stress. Horm Behav 2010;57:105e11. [4] Elenkov IJ, Chrousos GP. Stress systemeorganization, physiology and immunoregulation. Neuroimmunomodulation 2006;13:257e67. [5] Edwards KM, Burns VE, Carroll D, Drayson M, Ring C. The acute stressinduced immunoenhancement hypothesis. Exerc Sport Sci Rev 2007;35: 150e5. [6] Fast MD, Hosoya S, Johnson SC, Afonso LO. Cortisol response and immunerelated effects of Atlantic salmon (Salmo salar Linnaeus) subjected to short- and long-term stress. Fish Shellfish Immunol 2008;24:194e204. [7] Viveros-Paredes JM, Puebla-Perez AM, Gutierrez-Coronado O, SandovalRamirez L, Villasenor-Garcia MM. Dysregulation of the Th1/Th2 cytokine profile is associated with immunosuppression induced by hypothalamicpituitary-adrenal axis activation in mice. Int Immunopharmacol 2006;6: 774e81. [8] Weyts FA, Flik G, Rombout JH, Verburg-van Kemenade BM. Cortisol induces apoptosis in activated B cells, not in other lymphoid cells of the common carp, Cyprinus carpio L. Dev Comp Immunol 1998;22:551e62. [9] Pacak K, Palkovits M. Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 2001;22: 502e48. [10] Barton BA. Stress in fishes: a diversity of responses with particular reference to changes in circulating corticosteroids. Integr Comp Biol 2002;42:517e25. [11] Pacak K, Baffi JS, Kvetnansky R, Goldstein DS, Palkovits M. Stressor-specific activation of catecholaminergic systems: implications for stress-related hypothalamic-pituitary-adrenocortical responses. Adv Pharmacol 1998;42: 561e4. [12] Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999;79:1e71. [13] Sorensen C, Bohlin LC, Overli O, Nilsson GE. Cortisol reduces cell proliferation in the telencephalon of rainbow trout (Oncorhynchus mykiss). Physiol Behav 2011;102:518e23.
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Neuroendocrine mechanisms for immune system regulation during stress in fish Q4
s a, Mo nica Imarai b, Gino Nardocci a, Cristina Navarro a, Paula P. Corte ~ a-Castillo b, **, Margarita Montoya b, Beatriz Valenzuela b, Pablo Jara b, Claudio Acun a , * ndez Ricardo Ferna gicas y Facultad de Medicina, Universidad Andr Facultad de Ciencias Biolo es Bello, Santiago, Chile. Av. República 252, 8370134 Santiago, Chile Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile. Av. Libertador Bernardo n Central, 9170022 Santiago, Chile O'Higgins 3363, Estacio
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a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 February 2014 Received in revised form 10 July 2014 Accepted 3 August 2014 Available online xxx
In the last years, the aquaculture crops have experienced an explosive and intensive growth, because of the high demand for protein. This growth has increased fish susceptibility to diseases and subsequent death. The constant biotic and abiotic changes experienced by fish species in culture are challenges that induce physiological, endocrine and immunological responses. These changes mitigate stress effects at the cellular level to maintain homeostasis. The effects of stress on the immune system have been studied for many years. While acute stress can have beneficial effects, chronic stress inhibits the immune response in mammals and teleost fish. In response to stress, a signaling cascade is triggered by the activation of neural circuits in the central nervous system because the hypothalamus is the central modulator of stress. This leads to the production of catecholamines, corticosteroid-releasing hormone, adrenocorticotropic hormone and glucocorticoids, which are the essential neuroendocrine mediators for this activation. Because stress situations are energetically demanding, the neuroendocrine signals are involved in metabolic support and will suppress the “less important” immune function. Understanding the cellular mechanisms of the neuroendocrine regulation of immunity in fish will allow the development of new pharmaceutical strategies and therapeutics for the prevention and treatment of diseases triggered by stress at all stages of fish cultures for commercial production. © 2014 Published by Elsevier Ltd.
Keywords: Fish Neuroendocrine Immunology Stress Chromaffin cells Hypothalamus-pituitary-interrenal axis
1. Introduction The growing global demand for protein has led to the development of intensive aquaculture crops. However, the explosive growth experienced by this sector has been limited by a number of factors that have increased fish susceptibility to fatal diseases. It has been established that the constant biotic and abiotic changes that occur in cultured species induce physiological, endocrine and immunological responses in fish. These responses
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* Corresponding author. Laboratorio de Fisiología, Departmento de Ciencias gicas, Facultad de Ciencias Biolo gicas y Facultad de Medicina, Universidad Biolo s Bello, Av. República 252, 8370134 Santiago, Chile. Tel.: þ56 226615650. Andre ** Corresponding author. Laboratorio de Inmunoterapia, Centro de Biotecnología Acuícola, Universidad de Santiago de Chile, Av. Libertador Bernardo O'Higgins 3363, n Central, 9170022 Santiago, Chile. Tel.: þ56 227181169. Estacio ~ a-Castillo), rhfdez@gmail. E-mail addresses: [email protected] (C. Acun com, [email protected] (R. Fern andez).
help to mitigate the effects at the cellular level and maintain the internal environment (homeostasis). Different processes participate in preserving the physiological balance or allostasis. These process integrate autonomic, neuroendocrine, metabolic and behavioral components [1]. When an adequate adaptation response fails, the individuals generate an allostatic overload that produces pathological conditions [2]. The response to stimuli that generate an imbalance in the allostasis of an organism is known as stress, and the stimuli that generate it are called stressors [3]. For many decades, we have studied the effects of stress on the immune system in animal models [4]. While acute stress can have beneficial effects, chronic stress inhibits immune responses in both mammals and teleost fish [5e8]. Examples of stressors include physical (i.e., noise, vibration, pain, shock, temperature), psychological (i.e., exposure to a new or uncontrolled environment) and social (i.e., space availability). There are also stressors generated in the body that involve the cardiovascular system and metabolic homeostasis (i.e., hemorrhage,
http://dx.doi.org/10.1016/j.fsi.2014.08.001 1050-4648/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Nardocci G, et al., Neuroendocrine mechanisms for immune system regulation during stress in fish, Fish & Shellfish Immunology (2014), http://dx.doi.org/10.1016/j.fsi.2014.08.001
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exercise, heat exposure) [9]. Despite of this, individuals have general mechanisms in response to stress (Fig. 1), which involve a signaling cascade triggered by the activation of neural circuits in the central nervous system (CNS), such as cortical, limbic and hypothalamic structures (primary response [10]). In this response, the hypothalamus is the central modulator of stress, and catecholamines, corticosteroid-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and glucocorticoids are essential neuroendocrine mediators for this activation [11,12]. Whether stress is prolonged in time, the activated pathways evoke alterations in metabolic and cellular functions, osmoregulatory disturbances, and changes in the immune function (secondary response). Specifically in fish, the dynamic equilibrium is constantly threatened by intrinsic and extrinsic stressors. For example, high densities, non-natural habitats and unusual “social situations”, such as the frequent handling (e.g., during vaccination procedures), transport, overeating and sub-optimal water quality (e.g., variable temperatures, waste products, chemicals environmental pollutants), may generate an allostatic overload that affects the normal behavior and physiology in susceptible individuals. All the stressors may trigger a chronic stress in these individuals and may cause an anorexia state, alterations in locomotor patterns, and increases in the cortisol levels in the plasma and the serotonin levels in the brain [13,14]. These responses may trigger a delay in growth and a consequent reduction in the size of the fish, which would eventually lead to lower protein content. These later changes in the whole animal are known as tertiary response. The stressors trigger a series of regulatory events that interfere with the normal function of the immune system [15,16] and facilitate a rapid pathogenic expansion. To prevent and effectively treat infectious diseases, it is necessary to understand the elaborate bidirectional communication between the neuroendocrine system and the immune system. This communication is required to address damage or injury. A well-regulated inflammatory response is essential for overcoming an infection. However, an excessive inflammatory response can cause the destruction of tissue. The mechanisms that trigger stress (e.g., exposure to a pathogen) induce energy redistribution as a result of the sustained increases of hormonal activity (e.g., cortisol). The increased hormonal activity causes suppression of the functions (i.e., immune system) that are “less important” when survival is at risk [17]. Despite of this, exist immunosuppressive mechanisms that can protect the host cells against the extensive action of the immune response [18].
Fig. 1. Perceived stressors act on fish central nervous system to evoke primary (acute), secondary (transition) and tertiary (whole animal, chronic) physiological and related effects.
2. Reflex control of inflammation in mammals: neuroendocrine-to-immune communication The stress response in mammals is an integrated physiological and psychological reaction, and neuroendocrine responses are key to overcoming adversity. Increasing evidence supports the hypothesis that “healthy organs behave as ‘biological oscillators', which couple to one another, and this orderly coupling is maintained through a communication network, including neural, humoral, and cytokine components” [19]. This coupling is established through shared receptors and signal molecules to ensure physiological homeostasis and survival. The best-studied example of immune-neuroendocrine communication in mammals is the interaction between the components of the hypothalamus-pituitary-adrenal (HPA) axis (Fig. 2A). This axis is driven by a neural signal originating in the paraventricular nucleus (PVN) [20] and the immune system. Both endotoxin (i.e., lipopolysaccharide, a component of Gram-negative bacteria) and cytokines stimulate HPA anti-inflammatory responses by the production of adrenal glucocorticoids [12] or by inhibiting prolactin secretion. Prolactin is a potent regulator of humoral and cellular immune responses during physiological and pathological states [21]. Thus, the HPA- or ‘stress-axis’ conveys stress stimuli from the brain to the periphery. A stress stimulus also increases sympathetic activity [22]. Evidence accumulated over the last 30 years suggests that norepinephrine (NE), which is the main neurotransmitter of the sympathetic nervous system, fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs in the following ways: i) primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervations; ii) upon stimulation, NE is released from the sympathetic nerve terminals in these organs; and iii) the target immune cells, such as lymphocytes and macrophages, express adrenergic receptors (AR, adrenoceptors) [23,24]. Adrenoceptors are G-protein coupled receptors. Adrenoceptors can be divided into a- and b-AR subgroups, which can be further subdivided into different subtypes. Neutrophils, mononuclear cells, natural killer cells and T- and B-lymphocytes express a- and b-AR.
Fig. 2. Schematic representation of (A) the hypothalamus-pituitary-adrenal (HPA) axis in mammals; and (B) the hypothalamus-pituitary-interrenal (HPI) axis in fish. CRH, corticosteroid-releasing hormone; ACTH, adrenocorticotropic hormone.
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However, b2-AR is the most important adrenoceptor with respect to the immune system. b2-AR activation increases cAMP concentrations, which can modulate cytokine expression by decreasing tumor necrosis factor (TNF)-a and increasing interleukin (IL)-8 [25]. Conversely, a2A-AR stimulation increases TNF-a gene expression in Kupffer cells and plasma TNF-a during sepsis [26]. Thus, AR stimulation through locally released NE or circulating catecholamines affects lymphocyte trafficking, circulation, and proliferation and modulates cytokine production and the functional activity of different lymphoid cells [23]. The CNS can also rapidly inhibit the release of macrophage TNFa and attenuate systemic inflammation responses acting through the vagus (parasympathetic) nerve. This physiological mechanism is termed the ‘cholinergic anti-inflammatory pathway’ [27]. In human macrophages cultured in vitro acetylcholine (ACh), the main vagal neurotransmitter inhibits LPS-induced the release of proinflammatory cytokines TNF-a, IL-1b and IL-6, but not increases the anti-inflammatory cytokine IL-10 [27,28]. In addition, vagus nerve electrical stimulation inhibits TNF-a production and prevents the development of shock in rats [27]. Recent work on the anatomical basis of the cholinergic antiinflammatory pathway indicates that the spleen is required for vagus nerve control of inflammation [29]. In splenectomized rats injected with endotoxin, the level of serum TNF-a is reduced by 70% and vagus nerve stimulation fails to further suppress TNF-a [30]. The spleen is innervated by the splenic nerve that originates in the celiac-superior mesenteric plexus, and the celiac branches of the vagus terminate at that location [31]. The splenic nerve is composed mainly of catecholaminergic fibers that terminate in close apposition to immune cells [32]. Thus, the effects of TNF-a production induced by vagus nerve stimulation are mediated by NE released from splenic nerve endings. These data confirm the importance of the adrenergic transmitters in the regulation of immune responses [24,33]. 3. Neuroendocrine and immune responses to stress in fish Teleost fish are amongst the oldest vertebrates and have an immune system similar to that of mammals. They have an innate defense and aspects of the adaptive immune system. As in mammals, teleost fish possess lymphoid organs, such as the thymus, spleen and kidney [34]. However, unlike higher vertebrates, fish do not have bone marrow or a lymphatic system [35]. Fish have a cellecell contact communication system, including soluble mediators such as cytokines, to direct the immune response and communicate the recognition of stressors (e.g., pathogens) and regulate the magnitude of the response. Moreover, the immune system acts as a sensor [36] that informs the CNS to trigger a neuroendocrine response. Thus, stress leads to neuroendocrine communication between the CNS, the autonomic nervous system and the hypothalamus-pituitary-interrenal (HPI) axis (Fig. 2B). These systems regulate the immune system and decrease immune function in fish when it is hyperactive [6]. This means that neuroendocrine system signals affect normal immune system function [37]. Teleost fish have developed an effective immune system. The first barrier that a pathogen must defeat is a biochemical barrier that prevents their invasion. The barrier consists of an integumental mucosa layer with antibacterial peptides such as lysozyme, lectins and proteases [38]. If the pathogens cross this biochemical barrier, there is an additional mechanism of defense composed of phagocytic cells similar to those found in mammals. These cells include macrophages, neutrophils and natural killer cells in addition to B- and T-lymphocytes [39,40]. It has been reported that a variety of these immunocompetent cells possess the
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molecular machinery to respond to neuroendocrine factors because they have receptors for neurotransmitters, neuropeptides and hormones [41,42]. Moreover, it has also been demonstrated that leukocytes synthesize neuroendocrine mediators [43]. The data indicate the presence of receptors and hormones in immune cells. Additionally, the receptors for the soluble mediators are present in the neuroendocrine system, and there is a relationship between immunostimulation and immunosuppression against stress. 3.1. The hypothalamus-pituitary-interrenal (HPI) axis Immune-endocrine interactions in fish and the central role of the HPI axis are well summarized elsewhere [44]. Briefly, when teleost fish are exposed to a stressor, the structure that acts as an intermediary between the neuroendocrine pathway and the immune system is the head kidney. The head kidney possesses both endocrine and immune functions. The chromaffin cells of the head kidney are located in the walls of the posterior cardinal vein. These cells produce catecholamines, whereas the interrenal cells produce cortisol. Thus, the head kidney is the functional analog of the mammalian adrenal gland [45]. Both lymphoid (B- and T-lymphocytes) and myeloid (phagocytic) cells are produced in the head kidney hematopoietic tissue, which makes it the functional analog of the mammalian bone marrow [35]. This organization facilitates a direct paracrine interaction between the hematopoietic and endocrine tissues in the head kidney [42,46]. The anatomical organization of the head kidney suggests that the mediators secreted by the brain-(para)sympathetic-chromaffin cell axis, such as epinephrine and NE, and cortisol secreted by the HPI establish a direct paracrine communication between the immune system cells and vice versa. Cortisol is the main hormone produced by the stimulation of the interrenal gland (in a similar manner to the stimulation of the adrenal cortex in humans) [47]. When stress signals are perceived, the hypothalamic region of the nucleus pre-opticus of the brain responds by releasing CRH into the pituitary. This signal is received by the CRH receptor subtype 1 (CRH-R1) on pituitary corticotropes from the pars distalis. The binding of CRH with its receptor stimulates ACTH release into the circulation [48,49]. Subsequently, ACTH stimulates the production and release of the main corticosteroid cortisol by interrenal cells of the head kidney. Cortisol exerts its effect on target cells by binding to the cytosolic glucocorticoid receptor (GR) [50]. The cortisol-GR complex translocates into the nucleus, where it binds to glucocorticoid responsive elements (GRE) and modifies gene expression [51]. As in mammals, both the GR and the mineralocorticoid receptor are capable of binding cortisol [52]. In contrast to mammals, fish have duplicate GR genes (GR1 and GR2) that are translated into functional proteins [51]. GR1 also exists in two alternative splice variants (GR1a and GR1b) [53,54]. Thus, there are four receptors capable of binding cortisol in fish: GR1a, GR1b, GR2, and MR. However, their ability to induce activation of downstream genes is dependent on the cortisol concentration [55]. Corticosteroids regulate multiple aspects of immune defenses in mammals and influence the secretion of pro- and antiinflammatory cytokines [4]. Similarly, cortisol receptors have been described in fish immune cells, and cortisol affects the immune response in common carp (Cyprinus carpio) [54,55], rainbow trout (Oncorhynchus kisutch), and gilthead sea bream (Sparus aurata) [56]. Cortisol acts through the GR to regulate differential and profound effects on the immune system in teleost fish. Several in vitro studies have shown that cortisol inhibits LPS-induced expression of acute phase protein serum amyloid S (SAA) and pro-inflammatory
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cytokines such as IL-1b, TNF-a, IL-12, and iNOS activity [6,48,57]. The expression of cytokines is important, because can affect the activity of the HPI axis [58] principally in acute stress. Studies of the innate immune response in vitro have shown that cortisol decreases the phagocytosis of head kidney cells from tilapia, common carp and silver sea bream (Sparus sarba) [59]. Cortisol also inhibited chemotaxis and phagocytosis in a goldfish macrophage cell line and strongly inhibited respiratory burst activity in a dose-dependent matter [60]. In agreement with these results, cortisol also inhibits the pro-oxidative activity of leukocytes from head kidney in golden sea bream [61]. Cortisol also inhibited the proliferation of a monocyte/macrophage cell line from rainbow trout [62] and induced programmed cell death (apoptosis) of macrophages from silver sea bream and Atlantic salmon (Salmo salar) [6]. These in vitro results have been confirmed by in situ experiments [15]. In S. salar, the immunosuppression mediated by the chronic administration of cortisol (simulating chronic stress) decreased the relative expression of Interferon (IFN) a-1, Heatshock proteins 70 (HSP70) and 90 (HSP90), SAA, and GR. These changes were accompanied by a higher prevalence of pathogens such as the infectious pancreatic necrosis virus (IPNV) [63]. Studies of the adaptive response in vitro have shown that cortisol reduces immunoglobulin (Ig) M secretion by lymphocytes isolated from the spleen, head kidney and blood from common carp [64]. Furthermore, in situ temperature stress decreases the antibody responses after immunization [46]. In addition, cortisol inhibits the proliferation and induces apoptosis of lymphocytes from the blood, head kidney, spleen and thymus [65]. This process is dependent on GR, and RU486 (mifepristone), a specific GR blocker, prevents these processes [66]. Stress-induced immunosuppression could be controlled based on knowledge of the interaction between the neuroendocrine and immune systems. In particular, the HPI axis may be altered at different levels to suppress the production or the effect of cortisol under stress conditions. Modulation is based in the established hierarchical control of the axis, where CRH plays a key role in the systemic response to stress by modulating corticotropes activity and ACTH production [67]. The main function of ACTH in fish is the regulation of the steroidogenesis of cortisol in the interrenal cells of the head kidney [17] as ACTH is the main stimulus for production [67]. In rainbow trout, the use of mifepristone decreases stressinduced cortisol secretion by reducing hypothalamic CRH mRNA expression [68]. Furthermore, the sympatho-adrenergic stimulation causes cortisol release during confinement [69]. The corticotropic action of CRH can be avoided by the administration of the non-selective antagonist of the CRH receptor, the CRF(9e41) a-helix [70]. Another hypothalamic factor is melaninconcentrating hormone (MCH). MCH is a strong inhibitor of basal and CRH-stimulated ACTH secretion [71,72]. In addition, rainbow trout acclimated to an environment with abundant light have higher circulating levels of MCH and ACTH in plasma and lower cortisol than fish acclimated to a dark environment [73,74]. MCH is a heptadecapeptide that mediates color changes in teleost fish (antagonist of the alpha melanocyte stimulating hormone a-MSH) [75], and its plasma levels are modified during stress conditions. In 1996, an orexigenic role for hypothalamic MCH in the regulation of food intake and energy balance in mammals was demonstrated [76]. The exogenous administration of either barfin flounder (Verasper moseri) or human MCH in goldfish produces an anorexigenic effect [77]. However, this anorexigenic effect is significantly lower than the effect of CRH on food intake and energy balance in fish during stress conditions. The anorexigenic effect of CRH during stress may be prevented by the action of CRF(9e41) a-helix or MCH if administered either directly or induced by changes in the fish photoperiod.
3.2. The autonomic nervous system In mammals, lymphoid organs are innervated by both sympathetic and parasympathetic nerve fibers [23,78,79], whose activation stimulate or inhibit the immune response. Furthermore, we also know that leukocytes express both cholinergic and adrenergic receptors [80]. However, little is known about the cholinergic system in fish. Our understanding of the cholinergic system in fish is less than our understanding of the adrenergic system, which is predominant in response to stress. Because catecholamine receptors of the sympathoadrenomedullary system are present on immune cells of teleost fish [81], it is possible to hypothesize a direct autonomic innervation of the fish immune system. In fact, many lymphoid tissues receive sympathetic innervation. For example, in coho or silver salmon (O. kisutch), the spleen is highly innervated by adrenergic fibers in the vasculature and parenchyma [82]. Several radioligand binding experiments have demonstrated the presence of b-ARs in the anterior kidney, spleen and peritoneal leukocytes of goldfish (Carassius auratus) [83]. b-ARs have also been found in membranes isolated from the head kidney and from spleen leukocytes of the American catfish (Ictalurus punctatus) [84]. These results are complemented with the sequencing and characterization of a1-AR in teleosts and facilitate the functional studies of the immune system and other tissues [85,86]. Considering the mediators involved in the functional interactions, the direct influence of sympathetic innervations on the immune system of teleost fish is exerted through of the binding of epinephrine and NE to their functional adrenoceptors, a-AR and bAR that are present in the cells of the immune system [81]. Catecholamines inhibit the innate and acquired immune response in various species of teleosts through the activation of b-AR. However, a-AR stimulation leads to the production of antibodies [81,87e89]. In tilapia (Oreochromis aureus), Chen and collaborators showed that catecholamines and cortisol induced by cold stress inhibit the phagocytic activity of leukocytes and decrease plasma levels of immunoglobulin M (IgM). Moreover, the combination of cortisol and isoproterenol (a non-selective b-AR agonist) have an additive effect in reducing phagocytosis in vitro [90]. In common carp (C. carpio), it was observed that the co-administration of adrenaline and zymosan A (an inductor of inflammation) reduced the percentage of monocytes/macrophages. Additionally, these treatments reduced the expression of CXCL8_L1 chemokine (a functional homolog of mammalian IL-8) and its receptors (CXCR1 and CXCR2), which influence leukocyte recruitment after stress [91]. Recently, Chadzinka et al. (2012) reported the sequence of b2aAR in common carp. b2a-AR mRNA is constitutively expressed in the brain, especially in the preoptic nucleus (homologous to the mammalian hypothalamus) and in immune organs. During the in vivo inflammatory response, b2a-AR expression was upregulated in the peritoneal leukocytes. Additionally, epinephrine inhibits the expression of pro-inflammatory cytokines, chemokines and their receptors in fish phagocytes cultured in vitro [42]. Finally, epinephrine may influence the inflammatory response via direct regulation of leukocyte migration and/or apoptosis during zymosan-induced peritoneal inflammation in common carp [91]. ~ a-Castillo Similar to mammals (reviewed by Fernandez & Acun in 2012 [24]), autonomic responses in fish can be influenced by the immune system through the cytokines produced by glial cells (e.g., astrocytes) in the CNS, which modulates neuroendocrine responses. The autonomic response can also be altered by peripheral signals that gain access to the CNS through the circumventricular organs, which are structures without bloodebrain barriers [92]. Conversely, catecholamine secretion from teleost chromaffin cells is regulated by a host of cholinergic and non-cholinergic pathways
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that ensure sufficient redundancy and flexibility in the secretion process to permit synchronized responses to a myriad of stressors [93]. 3.3. Other neuroendocrine-immune response modulators during stress It has been reported that other hormones participating in the hypothalamicepituitary axis are expressed in the cells of the fish immune system. These hormones include CRH [94], growth hormone (GH) and prolactin [95,96], in addition to the proopiomelanocortin (POMC)-derived peptides ACTH, b-endorphin and a-MSH [97]. Other hormones such as leptin I and leptin II were also found [48]. Interestingly, ACTH and ACTH receptor-like molecules are present during early development in immune tissues such as the thymus, spleen and the interrenal tissue [98]. ACTH has been implicated in increased oxidative burst activity in phagocytes [99]. CRH also induces a-MSH release from the pituitary. Both ACTH and a-MSH have been shown to have immunomodulatory effects. In thymic areas, POMC-derived peptides and cytokines colocalize with apoptotic cells and have a putative role in the selection and apoptosis of thymic lymphocytes [97]. In mammals, opiate alkaloids and endogenous opioid peptides exert their physiological and pharmacological actions through the following opioid receptors: the morphine-like receptor, mu (MOR, m, oprm), a delta receptor (DOR, d, oprd) and a kappa receptor (KOR, k, oprk). These receptors are expressed both on neuroendocrine cells and on leukocytes [100]. Opioids modulate both innate and acquired immune response. In fish, morphine administration affects nitric oxide production, chemotaxis and apoptosis of head kidney leukocytes from common carp cultured in vitro [101]. Additionally, in vivo experiments have shown that specific agonists of opioid receptors impair leukocyte migratory properties and cause reduced chemotaxis and reduced expression of chemokine receptors [102]. Opioids affect the activity of leukocytes and expression of inflammatory molecules both in vivo and in vitro by altering chemokines and chemokine receptors [103]. As in mammals, thyroid function in teleosts also affects the immune system. Early studies showed a decrease in the number of
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circulating leukocytes in hypothyroid fish, which could be restored by addition of thyroxin and human thyroid-stimulating hormone (TSH) [104]. Finally, sex steroids also could affect fish immunity. The androgen receptor is detected in salmonid lymphocytes and estrogen receptor-a is present in catfish leukocytes [105]. In acidophilic granulocytes from gilthead sea bream, which are the functional equivalent of mammalian neutrophils, estrogen signaling through the G protein coupled estrogen receptor (GPER) regulates granulocyte activation. GPER activation of acidophilic granulocytes in vitro reduces the respiratory burst and drastically alters the expression profile of several genes encoding major proand anti-inflammatory mediators. In addition, GPER signaling in vivo modulates adaptive immunity [106]. 4. Concluding remarks The explosive growth experienced by the fish-derived food sector has been limited by a number of factors that have increased the susceptibility of fish to diseases and death. Constant changes, including both biotic and abiotic alterations, affect species in culture and induce physiological, endocrine and immunological responses to mitigate those effects. To meet the increasing demand for animal proteins, aquaculture continuously requires new techniques to increase their production. The intensification of aquaculture practices has increased the levels of stress in the animals. Although fish possess well-developed immune and neuroendocrine systems, extensive research is needed to support the hypothesis that teleosts have evolved complex communication networks between healthy organs and systems that connect neural, humoral and cytokine components to achieve homeostasis. Therefore, the interactions among these systems are of special clinical and commercial interest. The activity of a single pathophysiological response in several disorders can lead to the suppression of opposite responses. This shows that when a condition activating one of these components occurs in response to stress, a variety of adaptive processes can lead to pathologic processes in the individual. When the stressor is acute and a short-term response is stimulated, the immune response of fish is to enhance innate function. Acute stress results in an increase in circulating leukocyte numbers.
Fig. 3. The effect of acute and chronic stress upon the immune system function.
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This phenomenon is related to the activation of the sympathetic nervous system and release of catecholamines, which mobilize both erythrocytes and leukocytes. If the stressor is chronic, the immune response is suppressed, and this increases the possibility of infection. It is believed that the harmful effects of stress on the immune response are preferentially mediated by the suppressive effects of glucocorticoids (i.e., cortisol) and are a consequence of the inability to adapt to chronic stressors. This may occur because coping with the stressor imposes an allostatic cost that may interfere with the required immune response (Fig. 3). Because the stress situations are energetically demanding, it is expected that other hormones involved in metabolic support will have an influence on immune function. As a result, GH, opioids and thyroid hormones also affect immune responses. It must be emphasized that unlike mammals, fish use a single organ called the head kidney as the primary site of cortisol (interrenal cells) and catecholamine (chromaffin cells) production in addition to hematopoiesis and antibody production. Thus, the direct paracrine interactions between the immune and neuroendocrine systems in this organ are critical. Understanding the cellular mechanisms of the neuroendocrine regulation of the immune response in fish will allow the development of new pharmaceutical strategies and therapeutics for the prevention and treatment of diseases triggered by stress at all stages of fish cultures for commercial production. Acknowledgments R. Fernandez is funded by FONDECYT 1120976 and UNAB DI~ a-Castillo, M. 354-13/R; G. Nardocci, by FONDECYT 3140414; C. Acun Imarai, M. Montoya, B. Valenzuela and P. Jara, by Consorcio de ~ a-Castillo is also Sanidad Acuícola CORFO 13CTE-21527; C. Acun funded by FONDECYT 1110734 and CORFO 13IDL1-18500; M. Montoya, by FIA PYT 2012-0023. References [1] McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav 2003;43:2e15. [2] McEwen BS, Gianaros PJ. Stress- and allostasis-induced brain plasticity. Annu Rev Med 2011;62:431e45. [3] McEwen BS, Wingfield JC. What is in a name? Integrating homeostasis, allostasis and stress. Horm Behav 2010;57:105e11. [4] Elenkov IJ, Chrousos GP. Stress systemeorganization, physiology and immunoregulation. Neuroimmunomodulation 2006;13:257e67. [5] Edwards KM, Burns VE, Carroll D, Drayson M, Ring C. The acute stressinduced immunoenhancement hypothesis. Exerc Sport Sci Rev 2007;35: 150e5. [6] Fast MD, Hosoya S, Johnson SC, Afonso LO. Cortisol response and immunerelated effects of Atlantic salmon (Salmo salar Linnaeus) subjected to short- and long-term stress. Fish Shellfish Immunol 2008;24:194e204. [7] Viveros-Paredes JM, Puebla-Perez AM, Gutierrez-Coronado O, SandovalRamirez L, Villasenor-Garcia MM. Dysregulation of the Th1/Th2 cytokine profile is associated with immunosuppression induced by hypothalamicpituitary-adrenal axis activation in mice. Int Immunopharmacol 2006;6: 774e81. [8] Weyts FA, Flik G, Rombout JH, Verburg-van Kemenade BM. Cortisol induces apoptosis in activated B cells, not in other lymphoid cells of the common carp, Cyprinus carpio L. Dev Comp Immunol 1998;22:551e62. [9] Pacak K, Palkovits M. Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 2001;22: 502e48. [10] Barton BA. Stress in fishes: a diversity of responses with particular reference to changes in circulating corticosteroids. Integr Comp Biol 2002;42:517e25. [11] Pacak K, Baffi JS, Kvetnansky R, Goldstein DS, Palkovits M. Stressor-specific activation of catecholaminergic systems: implications for stress-related hypothalamic-pituitary-adrenocortical responses. Adv Pharmacol 1998;42: 561e4. [12] Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999;79:1e71. [13] Sorensen C, Bohlin LC, Overli O, Nilsson GE. Cortisol reduces cell proliferation in the telencephalon of rainbow trout (Oncorhynchus mykiss). Physiol Behav 2011;102:518e23.
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