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Effects of stress and cortisol on the polarization of carp macrophages
Maciuszek, Magdalena ; Rydz, Leszek ; Świtakowska, Iga ; Verburg-van Kemenade, Lidy ; Chadzińska, Magdalena - \ 2019
Fish and Shellfish Immunology 94 (2019). - ISSN 1050-4648 - p. 27 - 37.
Carp - Cortisol - Head kidney - Monocytes/macrophages - Stress - Trunk kidney
In teleost fish, myelopoiesis is maintained both in the head (HK) and trunk kidney (TK), but only the HK holds the endocrine cells that produce the stress hormone cortisol. We now compared the effects of prolonged restraint stress (in vivo) and cortisol (in vitro) on the polarization of HK and TK-derived carp macrophages. Monocytes/macrophages from both sources were treated in vitro with cortisol, lipopolysaccharide or with both factors combined. In vivo, fish were challenged by a prolonged restraint stress. Gene expression of several markers typical for classical M1 and alternative M2 macrophage polarization, as well as glucocorticoid receptors, were measured. Cells from both sources did not differ in the constitutive gene expression of glucocorticoid receptors, whereas they significantly differed in their response to cortisol and stress. In the LPS-stimulated HK monocytes/macrophages, cortisol in vitro counteracted the action of LPS while the effects of cortisol on the activity of TK monocytes/macrophages were less explicit. In vivo, restraint stress up-regulated gene expression of M2 markers in freshly isolated HK monocytes/macrophages, while at the same time it did not affect TK monocytes/macrophages. Moreover, LPS-stimulated HK monocytes/macrophages from stressed animals showed only minor differences in the gene expression of M1 and M2 markers, compared to LPS-treated monocytes/macrophages from control fish. In contrast, stress-induced changes in TK-derived LPS-treated cells were more pronounced. However, these changes did not clearly indicate whether in TK monocytes/macrophages stress will stimulate classical or alternative polarization. Altogether, our results imply that cortisol in vitro and stress in vivo direct HK, but not TK, monocytes/macrophages to the path of alternative polarization. These findings reveal that like in mammals, also in fish the glucocorticoids form important stimulators of alternative macrophage polarization.
A role for CXC chemokines and their receptors in stress axis regulation of common carp
Pijanowski, Lukasz ; Verburg-van Kemenade, Lidy ; Chadzinska, Magdalena - \ 2019
General and Comparative Endocrinology 280 (2019). - ISSN 0016-6480 - p. 194 - 199.
Carp - CXC chemokines - CXC receptors - Stress
Although chemokines mainly function to activate leukocytes and to direct their migration, novel evidence indicates non-immune functions for chemokines within the nervous and endocrine systems. These include development of the nervous system, neuromodulation, neuroendocrine regulation and direct neurotransmitter-like actions. In order to clarify a potential role for chemokines and their receptors in the stress response of fish, we studied changes in the expression patterns of CXC ligands and their receptors in the stress axis organs of carp, during a restraint stress procedure. We showed that stress down-regulated the gene expression of CXCL9-11 (CXCb1 and CXCb2)in stress axis organs and up-regulated expression of CXCR4 chemokine receptor in NPO and pituitary. Moreover, upon stress, reduced gene expression of CXCL12a and CXCL14 was observed in the head kidney. Our results imply that in teleost fish, CXC chemokines and their receptors are involved in neuroendocrine regulation. The active regulation of their expression in stress axis organs during periods of restraint indicates a significant role in the stress response.
Stress differentially affects the systemic and leukocyte estrogen network in common carp
Szwejser, Ewa ; Pijanowski, Lukasz ; Maciuszek, Magdalena ; Ptak, Anna ; Wartalski, Kamil ; Duda, Malgorzata ; Segner, Helmut ; Kemenade, Lidy van; Chadzinska, Magdalena - \ 2017
Fish and Shellfish Immunology 68 (2017). - ISSN 1050-4648 - p. 190 - 201.
17β-estradiol - Aromatase - Carp - Estrogen receptors - Leukocytes - Stress
Both systemic and locally released steroid hormones, such as cortisol and estrogens, show immunomodulatory actions. This research gives evidence that circulating and leukocyte-derived estrogens can be involved in the regulation of the immune response in common carp, during homeostasis and upon restraining stress. It was found that stress reduced level of blood 17β-estradiol (E2) and down-regulated the gene expression of components of the “classical” estrogen system: the nuclear estrogen receptors and the aromatase CYP19, in the hypothalamus, the pituitary and in the ovaries. In contrast, higher gene expression of the nuclear estrogen receptors and cyp19a was found in the head kidney of stressed animals. Moreover, stress induced changes in the E2 level and in the estrogen sensitivity at local/leukocyte level. For the first time in fish, we showed the presence of physiologically relevant amounts of E2 and the substrates for its conversion (estrone – E1 and testosterone – T) in head kidney monocytes/macrophages and found that its production is modulated upon stress. Moreover, stress reduced the sensitivity of leukocytes towards estrogens, by down-regulation the expression of the erb and cyp19 genes in carp phagocytes. In contrast, era expression was up-regulated in the head kidney monocytes/macrophages and in PBLs derived from stressed animals. We hypothesize that, the increased expression of ERα, that was observed during stress, can be important for the regulation of leukocyte differentiation, maturation and migration. In conclusion, these results indicate that, in fish, the estrogen network can be actively involved in the regulation of the systemic and local stress response and the immune response.
Estrogen-dependent seasonal adaptations in the immune response of fish
Szwejser, Ewa ; Kemenade, Lidy van; Maciuszek, Magdalena ; Chadzinska, Magdalena - \ 2017
Hormones and Behavior 88 (2017). - ISSN 0018-506X - p. 15 - 24.
Aromatase - Endocrine disrupting compounds - Estrogen receptors - Estrogens - Fish - Season
Clinical and experimental evidence shows that estrogens affect immunity in mammals. Less is known about this interaction in the evolutionary older, non-mammalian, vertebrates. Fish form an excellent model to identify evolutionary conserved neuroendocrine-immune interactions: i) they are the earliest vertebrates with fully developed innate and adaptive immunity, ii) immune and endocrine parameters vary with season, and iii) physiology is constantly disrupted by increasing contamination of the aquatic environment.Neuro-immuno-endocrine interactions enable adaption to changing internal and external environment and are based on shared signaling molecules and receptors. The presence of specific estrogen receptors on/in fish leukocytes, implies direct estrogen-mediated immunoregulation. Fish leukocytes most probably are also capable to produce estrogens as they express the . cyp19a and . cyp19b - genes, encoding aromatase cytochrome P450, the enzyme critical for conversion of C19 steroids to estrogens.Immunoregulatory actions of estrogens, vary among animal species, and also with dose, target cell type, or physiological condition (e.g., infected/non-infected, reproductive status). They moreover are multifaceted. Interestingly, season-dependent changes in immune status correlate with changes in the levels of circulating sex hormones. Whereas E2 circulating in the bloodstream is perhaps the most likely candidate to be the physiological mediator of systemic immune-reproductive trade-offs, leukocyte-derived hormones are hypothesized to be mainly involved in local tuning of the immune response. Contamination of the aquatic environment with estrogenic EDCs may violate the delicate and precise allostatic interactions between the endogenous estrogen system and the immune system. This has negative effects on fish health, but will also affect the physiology of its consumers.
The immunomodulatory role of the hypothalamus-pituitary-gonad axis : Proximate mechanism for reproduction-immune trade offs?
Segner, Helmut ; Kemenade, Lidy van; Chadzinska, Magdalena - \ 2017
Developmental and Comparative Immunology 66 (2017). - ISSN 0145-305X - p. 43 - 60.
Evolution - Hypothalamus-pituitary-gonad axis - Immunity - Life history - Neuroendocrine - Reproduction - Trade-off - Vertebrate
The present review discusses the communication between the hypothalamic-pituitary-gonad (HPG) axis and the immune system of vertebrates, attempting to situate the HPG-immune interaction into the context of life history trade-offs between reproductive and immune functions. More specifically, (i) we review molecular and cellular interactions between hormones of the HPG axis, and, as far as known, the involved mechanisms on immune functions, (ii) we evaluate whether the HPG-immune crosstalk serves as proximate mechanism mediating reproductive-immune trade-offs, and (iii) we ask whether the nature of the HPG-immune interaction is conserved throughout vertebrate evolution, despite the changes in immune functions, reproductive modes, and life histories. In all vertebrate classes studied so far, HPG hormones have immunomodulatory functions, and indications exist that they contribute to reproduction-immunity resource trade-offs, although the very limited information available for most non-mammalian vertebrates makes it difficult to judge how comparable or different the interactions are. There is good evidence that the HPG-immune crosstalk is part of the proximate mechanisms underlying the reproductive-immune trade-offs of vertebrates, but it is only one factor in a complex network of factors and processes. The fact that the HPG-immune interaction is flexible and can adapt to the functional and physiological requirements of specific life histories. Moreover, the assumption of a relatively fixed pattern of HPG influence on immune functions, with, for example, androgens always leading to immunosuppression and estrogens always being immunoprotective, is probably oversimplified, but the HPG-immune interaction can vary depending on the physiological and envoironmental context. Finally, the HPG-immune interaction is not only driven by resource trade-offs, but additional factors such as, for instance, the evolution of viviparity shape this neuroendocrine-immune relationship.
Neuroendocrine-immune interaction : Evolutionarily conserved mechanisms that maintain allostasis in an ever-changing environment
Kemenade, Lidy van; Cohen, Nicholas ; Chadzinska, Magdalena - \ 2017
Developmental and Comparative Immunology 66 (2017). - ISSN 0145-305X - p. 2 - 23.
Blood brain barrier - Homeostasis - Leukocytes - Neuroendocrine-immune interaction - Psychoneuroimmunology - Receptor interaction - Stress axis
It has now become accepted that the immune system and neuroendocrine system form an integrated part of our physiology. Immunological defense mechanisms act in concert with physiological processes like growth and reproduction, energy intake and metabolism, as well as neuronal development. Not only are psychological and environmental stressors communicated to the immune system, but also, vice versa, the immune response and adaptation to a current pathogen challenge are communicated to the entire body, including the brain, to evoke adaptive responses (e.g., fever, sickness behavior) that ensure allocation of energy to fight the pathogen. This phenomenon is evolutionarily conserved. Hence it is both interesting and important to consider the evolutionary history of this bi-directional neuroendocrine-immune communication to reveal phylogenetically ancient or relatively recently acquired mechanisms. Indeed, such considerations have already disclosed an extensive "common vocabulary" of information pathways as well as molecules and their receptors used by both the neuroendocrine and immune systems. This review focuses on the principal mechanisms of bi-directional communication and the evidence for evolutionary conservation of the important physiological pathways involved.
A role for multiple estrogen receptors in immune regulation of common carp
Szwejser, Ewa ; Maciuszek, Magdalena ; Casanova-Nakayama, Ayako ; Segner, Helmut ; Kemenade, Lidy van; Chadzinska, Magdalena - \ 2017
Developmental and Comparative Immunology 66 (2017). - ISSN 0145-305X - p. 61 - 72.
17β-estradiol - Carp - Estrogen receptors - GPR30 - Immune response - Monocyte/macrophage
Estrogens are important for bi-directional neuroendocrine-immune interaction. They act via nuclear estrogen receptors (ERα and ERβ) and/or G-protein coupled receptor - GPR30.We found expression of ERα, ERβ and GPR30 in carp lymphoid tissues and head kidney monocytes/macrophages, neutrophils and lymphocytes. Interestingly, ERβ is also expressed in some head kidney lymphocytes but not in naive PBLs. Immune stimulation altered the cell type specific profile of expression of these receptors, which depends on both activation and maturation stage.This implies direct leukocyte responsiveness to estrogen stimulation and therefore in vitro effects of 17β-estradiol (E2) on reactive oxygen species (ROS) production in monocytes/macrophages were determined. Short-time incubation with E2 increased ROS production in PMA-stimulated cells. Results comply with mediation by GPR30, partially functioning via phosphoinositide 3-kinase activation.These results furthermore demonstrate that neuroendocrine-immune communication via estrogen receptors is evolutionary conserved.
|The role of estrogen receptors and aromatase in carp leukocyte activation
Szwejser, Ewa ; Maciuszek, Magdalena ; Ptak, Anna ; Segner, H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, Magdalena - \ 2016
Stress-induced adaptation of neutrophilic granulocyte activity in K and R3 carp lines
Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Irnazarow, I. ; Chadzinska, M. - \ 2015
Fish and Shellfish Immunology 47 (2015)2. - ISSN 1050-4648 - p. 886 - 892.
Common carp - IL-10 - NET formation - Neutrophilic granulocytes - Respiratory burst - Stress
Both in mammals and fish, stress induces remarkable changes in the immune response. We focused on stress-induced changes in the activity of neutrophilic granulocytes in the R3 and K lines of common carp, which showed differential stress responses. Our study clearly demonstrates that a prolonged restraint stress differentially affects the activity of K and R3 carp neutrophils. In the K line, stress decreased the respiratory burst, while in the R3 line it reduced the release of extracellular DNA. Surprisingly, the stress-induced changes in ROS production and NET formation did not correlate with changes in gene expression of the inflammatory mediators and GR receptors. In neutrophilic granulocytes from K carp, gene expression of the stress-sensitive cortisol GR1 receptor was significantly higher than in neutrophils from R3 fish, which will make these cells more sensitive to high levels of cortisol. Moreover, upon stress, neutrophilic granulocytes of K carp up-regulated gene expression of the anti-inflammatory cytokine IL-10 while this was not observed in neutrophilic granulocytes of R3 carp.Therefore, we can hypothesize that, in contrast to R3 neutrophils, the more cortisol sensitive neutrophils from K carp respond to stress with up-regulation of IL-10 and consequently reduction of ROS production. Most probably the ROS-independent NET formation in K carp is not regulated by this anti-inflammatory cytokine. These data may indicate a predominantly ROS-independent formation of NETs by carp neutrophilic granulocytes. Moreover, they underline the important role of IL-10 in stress-induced immunoregulation.
|Mechanisms involved in the formation of extracellular traps in granuloctyes and macrophages of common carp
Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
|GPR30 mediates estradiol-stimulated increase of respiratory burst in carp macrophages
Szwejser, E. ; Casanova-Nakayama, Ayako ; Maciuszek, Magdalena ; Segner, H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
|Melationin regulates migratory activity and apoptosis of carp phagocytes during inflammation
Kepka, M. ; Szwejser, E. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
|Immune and neuroendocrine regulation of inflammation in teleost fish
Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
|Melatonin regulates chemotaxis of carp phagocytes
Kepka, M. ; Szwejser, E. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
|Expression of nuclear and membrane estrogen receptors in/on lymphoid organs and leukocytes in common carp: indications for neuroendocrine-immune interaction via estrogens
Szwejser, E. ; Casanova-Nakayama, Ayako ; Kepka, M. ; Maciuszek, Magdalena ; Verburg-van Kemenade, B.M.L. ; Segner, H. ; Chadzinska, M.K. - \ 2015
A role for melatonin in maintaining the pro- and anti-inflammatory balance by influencing leukocyte migration and apoptosis in carp
Kepka, M. ; Szwejser, E. ; Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Developmental and Comparative Immunology 53 (2015). - ISSN 0145-305X - p. 179 - 190.
coupled receptor dimerization - messenger-rna expression - pineal hormone melatonin - innate immune parameters - common carp - dna-damage - in-vitro - neutrophilic granulocytes - glucocorticoid-receptor - phagocytic-activity
Melatonin is responsible for the synchronization of many physiological processes, including the immune response. Here we focus on the expression of melatonin MT1 receptors in/on leukocytes, and on the effects of melatonin administration on the inflammatory processes of carp. For the first time, we showed that fish leukocytes express MT1 receptors, implicating direct responsiveness to melatonin stimulation. Moreover, both in vitro and in vivo, melatonin modulated the immune response. The most potent effects of melatonin concerned the regulation of leukocyte migration. Melatonin reduced chemotaxis of leukocytes towards CXC chemokines in vitro. In vivo, during zymosan induced peritonitis, i.p. administration of melatonin reduced the number of neutrophils. This correlated with a melatonin-induced decrease of gene expression of the CXCa chemokine. Moreover, melatonin induced a decrease of the respiratory burst in inflammatory leukocytes. Although these data do suggest a potent anti-inflammatory function for this hormone, melatonin-induced inhibition of leukocyte apoptosis clearly indicates towards a dual function. These results show that also in carp, melatonin performs a pleiotropic and extra-pineal function that is important in maintaining the delicate pro- and anti-inflammatory balance during infection. They furthermore demonstrate that neuroendocrine–immune interaction via melatonin is evolutionary conserved.
Activity of the hypothalamus-pituitary-interrenal axis (HPI axis) and immune response in carp lines with different susceptibility to disease
Pijanowski, L. ; Jurecka, P.M. ; Irnazarow, I. ; Kepka, M. ; Szwejser, E. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Fish Physiology and Biochemistry 41 (2015)5. - ISSN 0920-1742 - p. 1261 - 1278.
The stress response transmitted by the HPA axis is one of the best examples of neuroendocrine–immune interactions that are critical for survival. Analogous to the situation in mammals, the stress response in fish is characterized by the activation of the hypothalamo–pituitary–interrenal axis (HPI). Effects of cortisol on the fish immune system comply with findings in mammals and suggest that the differences in sensitivity to stress will influence the immune response and as a consequence of survival. Therefore, we studied the stress response and its immunity-related effects in four different carp lines (R3, R3xR8, K and R2) that display a differential pathogen susceptibility. Previous studies indicate that R3xR8 and R3 carp are susceptible to bacterial and parasite infection, while R2 and K are relatively resistant to infection. Interestingly, the most striking effect of stress on leukocyte composition and activity was observed in the pathogen-resistant K carp, even though no robust changes in gene expression of stress-involved factors were observed. In contrast, R3 carp showed no spectacular stress-induced changes in their immunological parameters with concurrent significant activation of the HPI axis. Upon stress, the R3 carp showed up-regulation of crf, pomc and gr2 gene expression in the hypothalamus. Furthermore in R3 carp, at all levels of the HPI axis, stress induced the highest up-regulation of il-1ß gene expression. Although we are aware of the complexity of the interactions between stress and pathogen susceptibility and of the risk of interpretation based on correlations, it is noteworthy that the fish more susceptible to infection also exhibited the highest response to stress.
Production of inflammatory mediators and extracellular traps by carp macrophages and neutrophils in response to lipopolysaccharide and/or interferon-¿2
Pijanowski, L. ; Scheer, M.H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Fish and Shellfish Immunology 42 (2015)2. - ISSN 1050-4648 - p. 473 - 482.
toll-like receptors - cyprinus-carpio - signaling pathways - expression analysis - escherichia-coli - immune-response - lps recognition - gene-expression - fish - l.
Neutrophilic granulocytes and macrophages are crucial for the innate immune response against infections. They migrate into the focus of inflammation, where they efficiently bind, engulf and kill bacteria by proteolytic enzymes, antimicrobial peptides, reactive oxygen (ROS) and nitrogen (RNS) species. Moreover, activated neutrophils and macrophages can form extracellular traps (ETs). Fish neutrophils and macrophages are morphologically, histochemically, and functionally similar to their mammalian counterparts, but their significance for regulation of inflammatory responses and pathogen killing needs further elucidation. We compared the activity of head kidney monocytes/macrophages and neutrophilic granulocytes of common carp and established that upon lipopolysaccharide stimulation, not only neutrophils, but also carp monocytes/macrophages release extracellular DNA and are capable to form macrophage extracellular traps (METs). To clarify whether many specific LPS functions reported for piscine phagocytes might be due to impurities in the commonly used LPS preparations we studied expression of inflammatory mediators, release of DNA, ROS and RNS in cells stimulated with LPS or its highly purified form (pLPS). Also IFN-¿2 stimulation and its synergism with LPS/pLPS in stimulating expression of pro-inflammatory mediators was studied. Results substantiate that a classical stimulation of TLR4 by LPS may indeed be absent in carp as most of the classically reported LPS effects are abolished or diminished when pLPS is used. Interestingly, we also observed a potent IL-10 expression in neutrophilic granulocytes upon LPS stimulation, which, apart from their pro-inflammatory function, clearly indicates a role in restrictive control of the inflammatory reaction.
|Melatonin affects migration and apoptosis of carp inflammatory leukocytes
Kepka, M. ; Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2014
In: 27th conference of european comparative endocrinologists (CECE) 2014 abstracts & programme. - - p. 96 - 96.
|Stress response and activity of the hypothalamus-pituitary-interrenal axis (HPI axis) in carp lines with different susceptibility to disease
Pijanowski, L. ; Jurecka, P.M. ; Irnazarow, I. ; Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2014
In: Proceedings of the 27th conference of european comparative endocrinologists (CECE) 2014 abstracts & programme. - - p. 107 - 107.
The stress response is one of the best examples of neuroendocrine-immune interactions. Analogue to the HPA axis in mammals, the stress response in fish is characterized by activation the hypothalamo-pituitary-interrenal (HPI) axis, activation of which starts in the hypothalamic nucleus preopticus (NPO) releasing corticotropic releasing hormone (CRH). CRH stimulates the pituitary to release adrenocorticotropic hormone (ACTH) which is cleaved from pro-opiomelanocortin (POMC). ACTH stimulates release of cortisol from the head kidney. Interestingly, also the crucial pro-inflammatory cytokine IL-1b is involved in both immune and endocrine signalling during stress. Like in mammals, fish leukocytes express receptors for cortisol (GR) and effects of cortisol on the fish immune system generally comply with findings in mammals. This implies that a differential sensitivity to stress may influence the immune response and as a consequence survival. Therefore we studied the stress response in different carp lines that display a differential pathogen susceptibility (R3xR8 and R3 carp are susceptible to bacterial and parasite infection, while R2 and K are relatively resistant). After a stress paradigm of prolonged restraining glucose and cortisol levels were determined, as well as expression of genes involved in HPI axis activity. Stress induced significant increase of serum cortisol levels in all fish lines studied. Both basal and stress-stimulated cortisol levels were higher in the R3xR8 line than in R2, K and R3 fish. In R3 fish we observed stress-induced up-regulation of POMC and GR2 gene expression in the NPO, while in K fish restraining stress slightly down-regulated expression of POMC and GR genes both in NPO and pituitary. Furthermore, both in NPO and pituitary of R3 fish the highest up-regulation of IL- 1b gene expression was observed. Although we are aware of the complexity of the network of connections between stress and susceptibility to pathogens it is striking that the fish more susceptible to infection also exhibit a higher expression of stress related genes.