Well-being and immune response: a multi-system perspective

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ScienceDirect Well-being and immune response: a multi-system perspective Julie Lasselin1,2,3,6, Elena Alvarez-Salas4,6 and Grigoleit Jan-Sebastian5 Whereas it is well-established that inflammation and other immune responses can change how we feel, most people are still surprised to hear that, conversely, well-being and its violations also affect our immune system. Here we show that those effects are highly adaptive and bear potential for both research and therapeutic applications. The studies discussed in this review demonstrate that immunity is tuned by ones emotions, personality, and social status as well as by other life style variables like sleep, nutrition, obesity, or exercise. We further provide a short excursion on the effects of stress and depression on immunity and discuss acute experimental endotoxemia as a model to study the effects of well-being on the innate immune response in humans. Addresses 1 Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany 2 Department of Clinical Neuroscience, Division for Psychology, Karolinska Institutet, Nobels va¨g 9, 171 65 Solna, Stockholm, Sweden 3 Stress Research Institute, Stockholm University, Frescati Hagva¨g 16A, 106 91 Stockholm, Sweden 4 Molecular Neurophysiology, Department of Neuroscience Research, National Institute of Psychiatry, Calzada Me´xico-Xochimilco 101, Tlalpan, 14370 Me´xico, D.F., Mexico 5 Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, 10010N Torrey Pines Rd, La Jolla, CA 92037, USA Corresponding author: Jan-Sebastian, Grigoleit ([email protected]) These authors contributed equally to the manuscript.

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Current Opinion in Pharmacology 2016, 29:34–41 This review comes from a themed issue on Immunomodulation Edited by Fulvio D’Acquisto

http://dx.doi.org/10.1016/j.coph.2016.05.003 1471-4892/# 2016 Elsevier Ltd. All rights reserved.

An increasing body of literature is dealing with the effects of chronic stress and depression on inflammation and immune function [1,2] (see Box 1). In contrast to those pathological violations of well-being, much less is known about how positive emotional states and well-being shape our response to inflammatory stimuli [3]. The use of experimental inflammatory models, such as acute endotoxemia (i.e., intravenous administration of lipopolysaccharide, LPS), has shed light on the highly adaptive and Current Opinion in Pharmacology 2016, 29:34–41

differentiated behavioral and emotional responses coming along with inflammation [4,5] (Box 2). Here, we review recent work suggesting that, conversely, the immune system may react in a comparably sensitive and adaptive way to positive mental states and other forms of well-being.

Emotional well-being and immunity The effects of emotional well-being on immune functions are not extensively explored, and that may not surprise. Well-being is not well-defined and therefore difficult to quantify. Because of its often subjective nature there are no animal models for its study, and even in humans a reliable induction within an experimental setting is challenging. In demographic observations, it is usually intertwined with lots of other traits and environmental variables. In addition, research investigations normally focus on problems in order to solve them, while wellbeing rather reflects the absence of a problem. So why is it worth it, anyway? An important point to keep in mind when exploring immune functioning is that there is no general rule regarding which type of immune response may be considered ‘good’ or ‘bad’. A strong pro-inflammatory response, for example, bears more risk of collateral damage but also may provide faster or more effective pathogen clearance. Therefore, the best immune reaction is the most well-adapted and economic one, i.e. the reaction that provides the best cost–benefit ratio according to given circumstances [6]. Well-being is reflecting the entirety of those circumstances enabling our nervous systems to integrate and translate them into a language which the immune system can ‘read’, just as it is the case with stress (see Box 1). However, whereas stress is classically defined as a threat to homeostasis, we hypothesize that well-being, in contrast, may serve as a safety signal reordering the immune system’s priorities depending on social, health, security or nutritional status. This also brings potential pathological consequences in terms of maladaptation due to mismatches between the situations under which those systems once evolved and our modern lives.

How social status and personality traits shape immunity

How subtle and precise the adaptations of immune functioning to outer circumstances can be was demonstrated by Cole et al. [7]. These authors found that lonely individuals display a stronger activation of anti-bacterial and pro-inflammatory genetic pathways, while pathways www.sciencedirect.com

Well-being and immune response Lasselin, Alvarez-Salas and Jan-Sebastian 35

Box 1 Violations of well-being: stress and depression The effects of stress and depression on basal immune functioning are extensively reviewed elsewhere and are not the focus of this review (for more information on depression see [1,4,64]; for stress we recommend [2,65]). However, since we consider depression, acute stress, and chronic stress the most important pathological, physiological, and mal-adaptive violations of well-being, respectively, we decided to mention them here shortly. In addition, recent progress on the role of cortisol in immune functioning may be of great interest from a pharmacological perspective. Stress and cortisol release make excellent examples for the longunderestimated adaptive nature of psychoneuroendocrine–immune interactions. After being considered to be generally anti-inflammatory for decades, it now becomes more and more clear that cortisol also provide pro-inflammatory properties depending on the exact dose, location and timing of release or application [66]. And whereas the allegedly immunosuppressive effects of acute stress were believed to save energy in favor of an enhanced fight-or-flight reaction, many researchers today consider acute stress to be rather pro-inflammatory and immune-enhancing, preparing the immune system for an injury (e.g., by accumulating natural killer (NK) cells in the skin) [65]. Less clear are the effects of long-term stress on immunity. Chronic stress seems to have both pro and antiinflammatory components, with chronically increased levels of proinflammatory cytokines, a blunted response to cortisol and impaired cellular and anti-viral immunity [2]. Since the overall effects of chronic stress on the immune system appear to be rather detrimental, it is usually interpreted as maladaptive [65]. Strikingly, individuals objected to severe early life stress often display long lasting effects on immune functions, like increased levels of pro-inflammatory cytokines [67]. This may reflect a general adaptation of the immune system to an unpredictable and dangerous environment with poor social support. The fact that depression causes changes in immune parameters like basal cytokine levels and is bi-directionally intertwined with inflammatory conditions is now well established [1]. There is also evidence that such changes indeed may lead to a higher susceptibility to infection [68], whereas — as to our knowledge — experiments on the acute immune response of depressive individuals to endotoxemia are still missing. The observation that depression resembles a chronic form of sickness behavior and other commonalities like the finding that a relatively high number of riskgenes for depression are immune-related, led some researchers to the assumption that depression and immune functioning are closely related [4,64]. Interestingly, depression itself can again be induced or enhanced by stress and is marked by disturbances in normal cortisol release [69], making the triad consisting of the immune system, the depressed brain, and the HPA axis an attractive target for pharmacological interventions. Other examples for potentially pathologic immune-changes caused by a violation of emotional well-being include bereavement, which is associated with inflammatory changes probably contributing to increased cardiovascular risk [70], or attachment anxiety, which is associated with altered T Cell distributions [71].

promoting anti-viral-responses were favored in subjects not feeling lonely. This was interpreted as an adaptation to life situations with, respectively, higher risks of injury (and subsequent bacterial infection) due to the lack of external support or higher risk of viral infection caused by more frequent contacts with other individuals. A recent study is in line with those data and demonstrated its physiological relevance by showing increased levels of the pro-inflammatory cytokines interleukin (IL)-6 and tumor www.sciencedirect.com

Box 2 Experimental endotoxemia as a human model of acute inflammation The intravenous injection of lipopolysaccharide (LPS; endotoxin) is a well-studied model to elicit a transient inflammatory response of the innate immune system in human volunteers [72]. LPS is a cellmembrane component of gram-negative bacteria and detected by the pattern recognition receptor, toll-like receptor (TLR)-4, which is predominantly found on various cells of the innate immune system but also on other cell types such as endothelial cells, adipocytes, glial cells or neurons [73]. Upon its activation an inflammatory immune response is initiated, which is marked by activation of the transcription factor NFkB, release of pro and anti-inflammatory cytokines (see Figure 2A), activation of the hypothalamo-pituitaryadrenal (HPA) axis, raise in body-temperature and heart rate (see Figure 2B), altered leukocyte patterns in the blood stream and initiation of sickness behavior [4,5], all resembling the response to an actual bacterial infection (for a more detailed comparison of the responses to LPS injection, actual infection and other inflammatory stimuli in humans see [74]). When relatively low doses up to 2 ng/kg of body weight are employed, the elicited immune-reaction normally peaks around 1–3 h after the injection and is undetectable after 8 h [5,72,75] (see Figure 2). Despite some inter-individual variability, the experimental endotoxemia model provides reliable and relatively homogenous data, making it an excellent model to study an immune response in a standardized way and without presence of an actual pathogen. This raised the interest of psychoneuroimmunologists who, during the past decade, mainly used the model to explore the effects of an ongoing immune reaction on mood and cognitive function [5]. However, due to its reliability and the variety of available outcome measures, experimental endotoxemia should also be perfectly suited to explore the effects of well-being and other information coming from the central nervous system and further bodily systems on the innate immune response. Injection of LPS (i.v., i.p. or i.c.v.) is also frequently used to study immune functions in laboratory animals. However, it should be mentioned that in rodents far higher doses of LPS need to be employed and that the elicited reaction displays some differences to that observed in humans (e.g., in terms of cytokine release and fever response) [76].

necrosis factor (TNF)-a during the inflammatory immune response to experimental endotoxemia in subjects that reported feelings of social disconnection [8]. Further examples encompass the prediction of decreased pain tolerance during endotoxemia by negative affectivity [9], or the immune-modulatory effects of optimism and positive outcome expectancies [10,11]. Fredrickson et al. [12] found that even the attitude and the way emotional well-being is achieved may determine effects on immune parameters. Whereas a specific stress and inflammationrelated set of genetic pathways was inhibited in eudaemonic participants, this was not the case in equally well individuals with a more hedonic life-style. Emotional well-being and immune-response in research and therapy

To make clinical use of emotional well-being or to investigate its effects on immune function in an experimental setup like acute endotoxemia (Box 2), adequate methods are needed for eliciting it. Current approaches Current Opinion in Pharmacology 2016, 29:34–41

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often make use of traditional eastern exercise and meditation programs like Yoga, Tai Chi and Qui Gong or other relaxation techniques, with mainly anti-inflammatory results like a decrease in plasma levels of the clinical inflammatory marker, C-Reactive Protein (CRP), or IL-6 [13]. In addition, there is growing evidence that the use of music may provoke significant changes both in hormonal levels as well as cellular and humoral immunity, with a decrease in plasma cortisol levels and an increase of IgA levels as most consistently reported effects [14]. An intriguing example of how adaptations of our organism to mental states may be exploited to influence an immune reaction comes from a spectacular experiment in which human volunteers underwent a special training program enabling them to voluntarily modulate their cytokine response to experimental endotoxemia through activation of the sympathetic nervous system, and shift it to a more anti-inflammatory profile [15]. In particular, the training program included meditation, breathing techniques and exposure to cold. When injected with endotoxin and using the learned techniques, the trained subjects displayed higher and earlier increases in plasma epinephrine levels in comparison to the control group. This was associated with a higher increase in circulating concentrations of the anti-inflammatory cytokine, IL-10, and lower increases in pro-inflammatory cytokine levels, as well as fewer symptoms of sickness [15]. It is noteworthy that some of the employed techniques fit the concept of biofeedback, a set of tools and exercises to gain control over involuntary physiological activities. Biofeedback can be effective in the treatment of several diseases improving mood and attention and promoting feelings of well-being [16,17]. Moreover heart rate variability biofeedback has been successfully used to decrease autonomic dysfunction induced by LPS administration, enabling participants to reduce their sickness symptoms, although without an effect on levels of pro-inflammatory cytokines [18]. Interestingly, it appears that, in the study by Kox et al., optimism towards the outcome promoted the effects of the training described above [10]. Previous studies indicate the possibility to modulate the immune system by placebo mechanisms, in particular behavioral conditioning [19], but failed to show any effect of expectancies [20]. In addition, in an experiment aiming at conditioning the effects of acute endotoxemia (Box 2), only behavioral, but not cytokine, response to the conditioned stimulus could be evoked [21]. Studies assessing the effect of a special training programs may therefore be the first indication of a placebo effect, through expectation mechanisms, on the response to an immune challenge [10,15].

Well-being: a concept of multiple systems Well-being is not just about how we feel but how we are, encompassing various organ systems and homeostatic functions all connected to our immune system using various pathways (for an overview of these pathways, Current Opinion in Pharmacology 2016, 29:34–41

see Figure 1). As manifold are the potential threats to well-being and subsequently immune functioning through disturbances of those functions and systems. For this review we selected some of the most important to discuss them in further detail. Sleep and immunity

Sufficient amounts and quality of sleep are not only a prerequisite for general well-being but also for normal immune functioning with inflammatory processes adapting to and shaping sleep architecture [22]. In modern industrialized societies, where the solar day and the endogenous circadian clock are no longer synchronized, negative effects of chronic circadian misalignment appear, such as reduction in cortisol levels and increase in both inflammatory and anti-inflammatory serum cytokines production in baseline conditions [23]. In mice, circadian disruption by changing light and dark phases from 12 h to 10 h, led to complex alterations of the immune response to experimental endotoxemia both in the brain and in the periphery (e.g., blunted response in the periphery and hippocampus and an exaggerated response in hypothalamic IL-6 and TNF-a expression) [24]. In another recent study, the increased LPS-induced brain immune response generated after psychological stress was only evident when the stressor was applied during the light (inactive) phase [25]. Observations like these make it probable that the negative effects of shift working and other disruptions of normal sleeping behavior like poor health or mood impairments are at least in part due to immune dysregulation [26]. Nutritional well-being

The nutritional status determines resource availability both for the immune system and the organism as a whole and is therefore of major importance when fighting a pathogen. While fulfillment of energy resources may be beneficial, the chronic alteration of nutritional status may have deleterious consequences for the host’s body and may impair the response to infection. Altered nutritional status (e.g., obesity or omega-3 deficient diets) is associated with both physiological and emotional alterations of well-being [27,28]; in addition, it is related with modifications of baseline inflammatory processes [29,30], altered gut microbiota [31] and increased vulnerability to infection [32], which may indicate altered response to immune challenges. In Western societies, diets are classically highly deficient in omega-3 essential fatty acids, a characteristic that increases pro-inflammatory properties of the diet [33]. Importantly, it was shown that feeding mice with an omega-3 deficient diet leads to increased cytokine expression in the hippocampus after an immune challenge, which may underlie memory impairments observed in those animals [34]. Conversely, supplementing the diet with flavones (antioxidants and anti-inflammatory) is able to reverse depressive-like behavior after LPS administration in mice by the www.sciencedirect.com

Well-being and immune response Lasselin, Alvarez-Salas and Jan-Sebastian 37

Figure 1

Inmune challenge Inflammation Current Opinion in Pharmacology

Major organ, systems and pathways connecting well-being and immune/inflammatory response to pathogens. Well-being and immune or immune/ inflammatory responses interact with each other through different mechanisms. (1) In the central nervous system (CNS), neurotransmitters (e.g., serotonin or dopamine) systems are involved in emotional state and in the behavioral consequences of an immune challenge [65,77]. (2) The autonomic nervous system (ANS) is activated following an immune challenge [78] and the release of epinephrine inhibits the immune system [15]. (3) The hypothalamus-pituitary-adrenal axis, well-known as the ‘stress axis’, is activated during an immune challenge [79] and its effectors (glucocorticoids, GCs) have been shown to modulate the immune response when exogenously administered before the immune challenge [80,81]. (4) Skeletal muscle during contraction releases myokines into the bloodstream promoting an anti-inflammatory state, which influences metabolism in other tissues and organs [53]. (5) The gut appears also as an important player as alterations in gut epithelium can lead to LPS leakage into the circulation [82] and the gut–brain axis, notably through the vagus nerve, may represent one mechanism linking well-being and sickness response [40]. (6) The adipose tissue release adipokines and adipocytokines [29], which can impact immune functions and inhibiting immune response in obese rodents [83]. (7) Finally, the immune system itself can contribute to modification in immune response by a ‘priming’ phenomenon, for instance induced by the inflammatory state associated with e.g., obesity, nutritional deficiency or altered sleep. Blue arrows: neural pathways; orange arrows: humoral pathways; violet arrows: both (neural and humoral) pathways.

inhibition of brain pro-inflammatory cytokines (i.e., IL-1b and TNF-a) [35]. Other evidence for the importance of nutritional well-being on the immune response comes from gut microbiota. Since the 1990s there is increasing interest in gut microbiota as an important factor to maintain health in the host [36]. The interest in gut microbiota further increased when it came clear that it also plays an important role in emotional regulation and as functional link between immunity and behavior [37]. As an example for the potential clinical application of the link between gut microbiota, immune responses and emotional regulation, administration of prebiotics in mice was shown to alleviate LPSinduced anxiety by preventing the increase of cortical IL1b and serotonin 2A receptor expression [38]. Although most of these findings need to be verified in humans, a www.sciencedirect.com

growing number of studies also indicate the potential role of gut microbiota in depression vulnerability and inflammation in humans [39,40]. Overall, these findings support the importance of the diet in modulating well-being and immune response of an individual, and the possible therapeutic effects an adequate nutrition may provide to treat inflammatory conditions. Obesity

One of the most important nutrition-related pathologies worldwide is obesity. Obesity is known to be associated with increased prevalence and incidence of depression [41] and, in turn, depression predicts increased weight gain and the development of obesity [42]. The adipokines (e.g., leptin) and adipocytokines produced by the adipose Current Opinion in Pharmacology 2016, 29:34–41

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Figure 2

the effect of body weight on the in vivo response to LPS, but found no significant effect of body mass index on immune response. However, the range of body mass index in that study was limited to the normal and mildly overweight range, with only one obese subject [50].

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tissue have been hypothesized as potential factors involved in the physiopathology of obesity-related neuropsychiatric comorbidity [28,43]. The effect of obesity in modulating the response to infection has been mostly studied in rodent models and has been recently reviewed [44]. Despite some studies reporting a decrease or no change in LPS-induced fever, peripheral inflammatory response or behavioral manifestations in obese rodents in comparison to their lean controls [45], a majority of the reports suggest an increase and/or prolongation of the immune response induced by LPS [46,47]. In addition, the few studies that have been conducted in humans using ex vivo protocols also suggest obesity to be associated with an intensified response to an inflammatory challenge. Immune cells from obese subjects produced more inflammatory factors when stimulated with LPS compared to those from normal-weight controls [48,49]. To our knowledge, only one study has analyzed Current Opinion in Pharmacology 2016, 29:34–41

The other main component of the energy balance equation is energy expenditure with physical activity as a key player, which is involved in immune function regulation in nonchallenged conditions, after LPS stimulation, and in inflammatory diseases [51]. Like infection, exercise can also elicit a release of cytokines [52]. However, the profiles of such release are markedly different from those observed during infection. Overall, exercise (by means of muscle contraction) promotes an anti-inflammatory profile, with a reduction in systemic TNF-a production and release, mainly through the action of epinephrine and muscle IL6 [53,54] and modifications in metabolic pathways. Chronic exercise inhibits obesity-induced NF-kb pathway activation and improves insulin signaling on different tissues, and decreases expression of TLR4 in adipose tissue by suppression of macrophage infiltration [55,56]. Although IL-6 has been considered as a pro-inflammatory cytokine, sufficient evidence exist regarding its anti-inflammatory role during exercise (as reviewed in Pedersen et al. [57]). Increased IL-6 levels during exercise appear to protect against diseases that course with low-grade inflammation [58]. Furthermore, voluntary wheel running in aged mice has been shown to prevent LPS-induced reduction in hippocampal neurogenesis by promoting a neuroprotective microglia phenotype [59]. In humans, exercise training alterations in inflammatory responses after LPS injection occur in a tissue-specific manner, enhancing inflammation in muscle and delaying it in the periphery and adipose tissue [60]. It is noteworthy that a recent meta-analysis on antidepressant effects of exercise clearly supports the success of moderate intensity aerobic exercise in improving symptoms of major depressive disorder in humans [61]. Thus, exercise makes an excellent therapeutic choice to promote general well-being and reduce inflammation in diseases associated with low-grade inflammation (i.e., obesity, type 2 diabetes) with considerably low sideeffects compared to pharmacological treatments [62].

Conclusion We have described here how modifications in well-being can modulate baseline immune parameters as well as the immune response to a pathogen. When trying to deduct a general rule for the actions of well-being on the immune system, those actions appear to be rather anti-inflammatory. This makes perfect sense considering well-being as a safety signal reporting stable energy, social, and health resources, conditions under which cell protection and repair or allocation of energy to other systems will dominate. On the contrary, impaired well-being may be indicative of a threat www.sciencedirect.com

Well-being and immune response Lasselin, Alvarez-Salas and Jan-Sebastian 39

to the organism including injury and infection. The response to that is an increase of the immune response and a shift towards a pro-inflammatory profile, sacrificing the aforementioned advantages in favor of pathogen clearance [63]. At least in highly-developed countries, the risk of infection is now markedly reduced compared to the past millennia over which the immune system evolved. In contrast, today dysregulations of the immune system like chronic inflammation, allergy or auto-immune disease are causing increasing problems. The growing knowledge on the immune-regulative effects of well-being may support prevention or therapy of such diseases. The use of exercise, relaxation techniques, better sleep hygiene, or nutritional improvements may enable patients to gain more control over their condition. And new insights into the action of glucocorticoids as well as the promising results from biofeedback and immunoconditioning studies may open up new therapeutic approaches for clinicians to supplement and refine pharmacological treatments. Nevertheless, reducing the adaptive nature of well-beingimmune interactions to a linear pro versus anti-inflammatory relation would lead to an incomplete picture. For instance, timing, intensity, chronicity, and the respective type and quality of the well-being alteration and the immune reaction may play a crucial role. In addition, it is not always clear in which context a certain decrease or increase of immune activation turns out to be beneficial or detrimental. To fully understand those powerful interactions in order to support beneficial adaptations of our immune system and prevent maladaptation, further controlled experimental studies with human subjects are needed. The model of acute experimental endotoxemia therefore provides a formidable choice for researchers interested in studying the effects of the central nervous system and other bodily systems or their pharmacological modifications on the acute inflammatory immune response.

Funding Nothing declared.

Conflict of interest Nothing declared.

Acknowledgements JL is funded by the Alexander von Humboldt Foundation (Germany), JSG is funded by a grant of the German Research Foundation (DFG; GR4370/11).

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Well-being and immune response Lasselin, Alvarez-Salas and Jan-Sebastian 41

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Comprehensive but easy-to-read review on the divergent actions of glucocorticoids on immune functions and the various receptors and mechanisms involved. 67. Miller GE, Chen E, Parker KJ: Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011, 137:959-997. 68. Andersson NW, Goodwin RD, Okkels N, Gustafsson LN, Taha F, Cole SW, Munk-Jorgensen P: Depression and the risk of severe infections: prospective analyses on a nationwide representative sample. Int J Epidemiol 2015, 45:131-139. 69. Gold PW: The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry 2015, 20:32-47. 70. Cohen M, Granger S, Fuller-Thomson E: The association between bereavement and biomarkers of inflammation. Behav Med 2015, 41:49-59. 71. Jaremka LM, Glaser R, Loving TJ, Malarkey WB, Stowell JR, Kiecolt-Glaser JK: Attachment anxiety is linked to alterations in cortisol production and cellular immunity. Psychol Sci 2013, 24:272-279. 72. Bahador M, Cross AS: From therapy to experimental model: a hundred years of endotoxin administration to human subjects. J Endotoxin Res 2007, 13:251-279. 73. Garcia Bueno B, Caso JR, Madrigal JL, Leza JC: Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev 2016, 64:134-147. 74. Shattuck EC, Muehlenbein MP: Towards an integrative picture of human sickness behavior. Brain Behav Immun 2016. (in press). 75. Lasselin J, Elsenbruch S, Lekander M, Axelsson J, Karshikoff B, Grigoleit JS, Engler H, Schedlowski M, Benson S: Mood disturbance during experimental endotoxemia: predictors of state anxiety as a psychological component of sickness behavior. Brain Behav Immun 2016. 76. Munford RS: Murine responses to endotoxin: another dirty little secret? J Infect Dis 2010, 201:175-177. 77. Pomytkin IA, Cline BH, Anthony DC, Steinbusch HW, Lesch KP,  Strekalova T: Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance? Behav Brain Res 2015, 276:111-117. Interesting paper that links alteration in peripheral serotonergic system leading to endotoxemia. Subsequent inflammation can trigger factors of both depression and diabetes. 78. Scanzano A, Cosentino M: Adrenergic regulation of innate immunity: a review. Front Pharmacol 2015, 6:171. 79. Bellavance MA, Rivest S: The HPA – immune axis and the immunomodulatory actions of glucocorticoids in the brain. Front Immunol 2014, 5:136. 80. Yeager MP, Rassias AJ, Pioli PA, Beach ML, Wardwell K, Collins JE, Lee HK, Guyre PM: Pretreatment with stress cortisol enhances the human systemic inflammatory response to bacterial endotoxin. Crit Care Med 2009, 37:2727-2732.

64. Miller AH, Raison CL: The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2015, 16:22-34.

81. Frank MG, Miguel ZD, Watkins LR, Maier SF: Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun 2010, 24:19-30.

65. Dhabhar FS: Effects of stress on immune function: the good,  the bad, and the beautiful. Immunol Res 2014, 58:193-210. A surprising and entertaining evolutionary perspective on the effects of stress on immune functions.

82. Kaliannan K, Wang B, Li XY, Kim KJ, Kang JX: A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia. Sci Rep 2015, 5:11276.

66. Cruz-Topete D, Cidlowski JA: One hormone, two actions:  anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 2015, 22:20-32.

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Current Opinion in Pharmacology 2016, 29:34–41