Current Pharmaceutical Design - Volume 20, Issue 29, 2014

Today it is recognized that the regulatory systems namely nervous, endocrine and immune systems, do not function independently but are intimately linked, constituting a psychoneuroimmunoendocrine system. The communication between these physiological systems, is the basis of the maintenance of homeostasis and therefore of health. Each of these homeostatic systems is complex and more so, the interactions between them. Currently, there is abundant work that confirms this bidirectional communication, which depends on the following facts: A) The cells of each of the three systems can express receptors for the mediators of the others, namely cytokines, hormones and neurotransmitters; B) Immune, nervous and endocrine products coexist in lymphoid, endocrine and neural tissue; C) Endocrine and neural mediators can affect the immune system; and D) Immune mediators can affect endocrine and neural functions. These bidirectional communications may happen in long or short loops. With respect to the long loops, the effect of mediators of nervous and endocrine systems on the immune cells was possibly the easiest aspect to understand, since both primary and secondary immune organs, are innervated and irrigated. It was more difficult to accept that immune mediators, such as cytokines, can arrive to the brain. In fact, mediators produced by peripheral immune cells reach the Central Nervous System (CNS), and the leukocytes even being able, in specific situations, to pass through the blood-brain barrier. Nevertheless, the CNS can show an immune response using its resident cells such as glial cells, ependymal cells or neurons. At the level of short-loop interactions, the capacity of production of typical neurotransmitters and hormones by immune cells, as well as of cytokines by nervous and endocrine cells, was also difficult to accept, not only at peripheral level, but also in the brain. Currently, the improved knowledge of this communication between homeostatic systems constitutes the scientific basis, which allows us to understand many facts of everyday life. Thus, it is well known that situations of emotional stress or anxiety are accompanied by a greater vulnerability to conditions ranging from infectious processes to cancer or autoimmune diseases, agreeing with the concept that the immune system is impaired. By contrast, pleasant emotions and a “positive outlook” on life help us to overcome immune system-related diseases and enjoy better overall health. Conversely, it has been shown that immune system changes, such as those found in infectious processes, alter the functions of the nervous system, which could lead, if those changes are not well controlled, to psychotic disorders and neural diseases. Thus, we must take into consideration that health is the result of the appropriate functioning of homeostatic systems as well as the perfect balance of mediators produced by them. When one of these mediators is overproduced or released in lower amounts than those necessary, the pathology appears. Any process is good or bad for health depending on the context, the amount of mediators, the period of time in which it is developing, etc. For example, inflammation is essential for survival since it serves to eliminate dangerous intrinsic and extrinsic factors and mediates tissue repair. However, this process requires a tight control exerted by anti-inflammatory cytokines. When the inflammation is uncontrolled many pathologies occur. In the current issue 15 different aspects of this psychoneuroimmunoendocrine communication will be presented by experts in the field, bringing together the most recent and novel studies available. Moreover, on reading several reviews in this issue some new physiological, pathological and therapeutic ideas will be discussed opening our mind to new ways of understanding health and sickness. It is possible that the response to stress situations, which are an integral part of daily life, is one of the best examples to understand the communication between the homeostatic systems. The stress response is essential for survival and when this is not adequate, due to bad crosstalk between the three regulatory systems, health can be compromised leading to the development of a pathology. In the article of Cruces et al. [1] the effects of stress, and especially psychological stress, on the nervous, endocrine and immune systems are covered. Moreover, social isolation, an important cause of psychological stress, provokes a deterioration of the psychoneuroimmunoendocrine system and thus may increase morbidity and mortality. In fact, this increase has been commonly observed in individuals following the death of their partner. Nevertheless, these deleterious effects depend on the individual’s reaction, for example whether the subject shows anxiety or not, in this stress situation. Maternal deprivation, a model of isolation in the early stages of life, is another example of the effects of stress disrupting the communication between the homeostatic systems. As another concrete example of how a psychological stress situation affects the neuroimmunoendocrine communication the study of Palermo- Neto and Alves [2] deals with the effects produced by cohabitation with a sick partner. Since this subject has not been sufficiently studied in caregivers of sick persons, and the results obtained in rodent models appear to be similar to those in humans, the authors propose a rodent model, which permits a deeper study of the mechanisms involved in the response to this psychological stress. A very interesting subject, which is not frequently considered in physiological studies, is the circadian system, which could be a relevant part of the homeostatic complex that represents the neuroimmunoendocrine system. In fact, this system shows circadian as well as circannual or seasonal variations in most of its variables. The aging process is another biological rhythm. With aging, an impairment of the homeostatic systems occurs and an alteration in the control of circadian and circannual rhythms has been demonstrated. This regulation of the homeostatic systems, especially that of the immune system, by biological rhythms as well as its age-related dysregulation, which compromise the quality of life of individuals, is covered by Maté et al. [3]. In this review it is shown how several immune function parameters, which are good markers of health and of the rate of aging, change not only with age (immunosenescence) but also throughout the day and year. Thus, the immune functions during the early afternoon show values more similar to those of older subjects than during the morning. In addition, in winter, especially in the case of mature men and women, the immune cell function show the most significant impairment. The role of immunomodulatory hormones, such as melatonin, in the regulation of biological rhythms and their involvement in the aging process is noteworthy. Furthermore, the evidence of regulation of the circadian system by the immune system and its disturbance with aging, is also mentioned, highlighting the importance of proinflammatory cytokines in this complex cross-talk. In addition to age, in some diseases the biological rhythms can be impaired. This and the use of chronotherapy are other relevant aspects encompassed in this review. To understand the mechanisms underlying the impairment of homeostatic systems it is necessary to know how oxidative stress and inflammatory stress are involved. In the review by Vida et al. [4] this subject is covered, highlighting the oxidative-inflammatory stress in the regulatory systems, which occurs with aging and anxiety, two very related situations. In fact, in a model of premature aging in mice, in which animals show a poor response to stress and high levels of anxiety, an oxidative stress in their immune cells and tissues occurs, as well as a premature immunosenescence and a shorter life expectancy. This model supports the hypothesis that anxiety can be a situation of chronic oxidative stress and inflammation, especially in brain and immune cells, and this accelerates the rate of aging. Nitric oxide (NO) is a significant molecule involved in oxidative stress. NO can be transformed into highly reactive and harmful molecules producing an impairment of the bio-molecules (DNA, lipids or proteins), altering their function. Thus, NO shows an important role in many pathological processes, but also in many physiological functions, including those of a mediator of blood vessel dilation, neurotransmitter, neuromodulator and inductor of mitochondrial biogenesis. The dual action of NO and its role in homeostasis, especially in the nervous and immune systems, is reviewed by Rocha et al. [5]. As mentioned above, an aspect of neuroimmunoendocrine communication, is the production by immune organs of molecules with hormonal functions. In the review by Reggiani et al. [6], the physiological and therapeutic roles of thymulin, a thymic hormone, are covered. Moreover, studies that show how the production and secretion of thymulin is strongly influenced by the neuroendocrine system are mentioned. These represent examples of how mediators of the nervous and endocrine systems can affect immune organs. The endocannabinoid system constitutes a relevant example of molecules produced by both brain and immune cells. This system has as its main function the maintenance of body homeostasis. The role of this in the hypothalamic-pituitary axes in their responses to inflammation and infection has been extensively reviewed by De Laurentiis et al. [7]. These authors also covered the potential pharmacological therapies based on the manipulation of the components of this endocannabinoid system, which could provide novel treatments for many disorders. More information on the cannabinoid system as well as its role in inflammation as a neuro-protective system, is shown in the review by Hernangómez et al., [8]. These authors demonstrate the importance of innate immunity response within the CNS and the role that this response plays, when it is uncontrolled (with macrophages and microglia as important participants), in the development and expansion of autoimmune and neurodegenerative diseases. Primary examples of these are multiple sclerosis (MS) and Alzheimer's disease (AD). In the regulatory mechanisms involved in the control of this CNS innate immunity, the neuroimmune regulatory proteins (NIReg) are relevant. Concretely, in this review the role of CD200 and its receptor CD200R, in silencing and reshaping an adverse innate immune response, is emphasized. Thus, CD200-CD200R as an anti-inflammatory and neuroprotective pair in MS, is highlighted. In addition, the role of CD200-CD200R in aging brain and in Alzheimer´s disease (AD) is reviewed. Moreover, the possibility that endocannabinoids can be used as therapeutic targets for promoting CD200-CD200R interaction is proposed for the above mentioned diseases. Alzheimer´s disease (AD) is widely considered in the review by Gimenez-Llort et al. [9]. This disease can be better understood in the context of the aging of the neuroimmunoendocrine system. These authors show evidence of the relevance of the disruption of the cross-talk between the cells of the homeostatic systems and their mediators from the prodromal stages of AD, when cognitive function still seems apparently normal. This disruption contributes to the onset of disease, and to know this, may help us to understand its biological mechanisms and to find behavioral and immunological biomarkers for the prodromic phases. Moreover, the use of lifestyle strategies such as physical exercise, environmental enrichment and nutrition to improve the nervous and immune functions in animal models for this disease is highlighted in the review. As previously stated, all the homeostatic system mediators have to be present in the appropriate amount and their production and release must take place with a perfectly controlled spatial and temporal pattern. As an example of this Besedovsky and Del Rey [10] show what happens with IL-1, the pro-inflammatory cytokine most studied in the context of nervous-immune communication. Among the different physiological effects of this cytokine, its role in re-setting glucose homeostasis, in the peripheral and brain levels, is emphasized in this review. The authors mention the capacity of IL-1 to deviate glucose to immune cells during inflammatory and infectious diseases as one of the bases of metabolic control produced by the immune system. Several mechanisms are involved in the deviation of the physiological functions of IL-1 to pathology. Thus, depending on the amount of this cytokine, physiological or diabetogenic effects are produced. The role of bacterial infections and the possible aberrant activation of the inflammatory response and the consequent disease are covered in the following reviews. Burdet et al. [11] review the case of pregnant women, and how maternal infections and inflammation can produce premature labor. How bacteria invade the uterine capacity, which is normally a sterile environment, is a very interesting subject. This, and the reasons why different species of bacteria vary in their capacity to induce inflammation and preterm birth, are covered in this review as well as possible therapeutic interventions. The review by Rettori et al. [12] shows periodontitis as another chronic inflammatory complex problem caused by microorganisms. This disease, characterized by the progressive destruction of the tooth and its support leading to tooth loss, has a possible impact on general health, and the balance of the host neuro-immuno-endocrine responses is altered. The possible link between periodontitis and diabetes, cardiovascular diseases, strokes and metabolic syndromes, all sharing a common denominator that is inflammation and oxidative stress, is covered. In addition, the negative effects of stress on this disease, the effects of oxytocin in modulating the individual response to stress, and the participation of components and functions of the endocannabinoid system with anti-inflammatory actions on gingiva, are also mentioned. As another concrete example of the involvement of the reciprocal interactions between the neuroendocrine and immune systems in a pathological situation, Hauk et al. [13] review an inflammatory disorder, the Sjögren syndrome (SS), in which a progressive loss of salivary and lacrimal gland secretions occurs. The effects of the neurotransmitter vaso intestinal peptide (VIP) and its receptor (VPAC) using a model of SS, non obese diabetic (NOD) mice, showing the physiopathological mechanisms of this disease, are mentioned in this review. The microbiota present in the gut and the gut-brain-immune system axis are extensively dealt with by Martín-Villa [14]. In this context, the author explains the etiology of two major inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. Recent data suggest that these diseases are an exaggerated mucosal immune response to microbiota present in the gut, in which T lymphocytes play a crucial role in the pathogenic events leading to tissue damage. These diseases are the result of psychological trauma, stress or depression, acting on genetically predisposed individuals. Thus, these diseases are an example of how emotional stress could increase epithelial permeability, modify the gut microbiota composition and activate pre-sensitized T lymphocytes, showing the link between emotions, microbiota and immune functions. Following the relevant role of micro-organisms, especially those in gut, the last review of this issue by Montiel-Castro et al. [15] deals with a very novel and interesting subject such as the effect of the microbiota-gut-brain axis on social interactions. The first part of the article describes concepts of behavior and nervous system function. This is followed by how different neurological processes are the base of socialdecision making and how the regulation of different aspects of animal behavior is carried out. Finally, the authors suggest the involvement of microbiota in the social interactions of each individual. The idea that microbiota are our closet partners interacting with gut immune and nervous systems, and these with the central nervous system, and how these microbiota can modify our behavior is a new field in psychoneuroimmunoendocrinology. The collection of articles in this issue of CPD allows the reader to bring their knowledge of psychoneuroimmunoendocrinology up to date. This is a novel field of research not frequently found in scientific publications. Moreover, it should be stated that any pharmaceutical intervention designed to improve health will affect the three regulatory systems and their communication. Thus, the contributions to this issue highlighting original aspects of this field could lead to a better understanding of our prospects of health.

The adaptive response to physical or psychological challenges or threats involves the modulation of the three regulatory systems: the nervous, endocrine and immune systems. Correct communication between these systems is required to maintain a homeostatic balance, and to guarantee the health and survival of the individual. While the stress response is essential for survival, failure to cope with a stress can impair the function of these regulatory systems and prevent effective communication between them. Under such circumstances, the loss of homeostasis ultimately leads to the development of pathologies that can compromise survival. Social species live in groups, the maintenance of which ensures the survival of the individual by providing protection from environmental threats. However, the disruption of social bonds in such species constitutes a potent emotional stress. Thus, social isolation is considered a risk factor for morbidity and mortality. The response to isolation or loneliness can vary greatly between individuals due to the influence of many factors, some of which will be considered in this Review. These factors can exert a significant influence on the three regulatory systems throughout the lifespan of the organism, and they include characteristics of the stressor itself (e.g., duration), as well as those of the organism (e.g., biological age), in addition to external factors (e.g., environmental events).

This study reviews the neuroimmunological consequences elicited in mice from long-term cohabitation with tumor-bearing conspecifics. Two types of experiments were performed; one used Swiss female mice and Ehrlich tumor cells, and the other used C57Bl/6 female mice and B16F10 melanoma cells. The female Swiss mice and the C57Bl/6 mice were divided into two groups, i.e., control and experimental. One mouse in each control pair was treated with control solutions (1.0 mL/kg); the other was kept undisturbed and called the ‘companion of health partner’ (CHP). One mouse in each experimental pair was inoculated with 5 x 106 Ehrlich tumor cells or with 106 murine B16-F10 melanoma cells; the other mouse, which was the subject of the performed studies, was left undisturbed and called the ‘companion of sick partner’ (CSP). Although we used two different strains of mice and two different tumor types, the CSP mice presented, in relation to the CHP mice, an increased locomotion in the open field and plus maze apparatuses and no changes in the corticosterone serum levels before and after the immobilization-stress challenge. The Swiss CSP mice showed a reduced level and an increased turnover rate of hypothalamic noradrenaline (NE), as well as increased plasmatic levels of adrenaline and NE. Changes in the immune cell phenotype and activity were also observed in the Swiss and C57Bl/6 CSP mice. The study found that odor cues left by the Ehrlich tumor-injected Swiss mice are aversive and may therefore be responsible for the neuroimmune changes reported in the CSP mice. It is proposed that the final neural link between the neuroimmunological changes observed in the CSP mice involves psychogenic stress imposed by the housing condition and the activation of the brain catecholaminergic pathways and the sympathetic nervous systems.

The health maintenance depends on the preservation of the homeostatic systems, such as nervous, endocrine and immune system, and a proper communication between them. In this regard, the circadian system, which promotes a better physiological system functions and thus well being, could be considered part of that homeostatic complex, since the neuroimmunoendocrine system possesses circadian patterns in most variables, as well as circannual or seasonal variations. With aging, an impairment of the homeostatic systems occurs and an alteration of circadian system regulation has been demonstrated. In the immune system, several function parameters, which are good markers of health and of the rate of aging, change not only with age (immunosenescence) but also throughout the day and year. Indeed, with advancing age there is a modification of immune cell circadian function especially in lymphocytes. Moreover, immune functions at early afternoon correspond to more aged values than at morning, especially in mature subjects (60-79 years of age). In addition, these mature men and women showed a significant impaired immune cell function, which is especially remarkable in the winter. It is noteworthy the role of immunomodulatory hormones, such as melatonin, in the regulation of biological rhythms and their involvement in the aging process. Furthermore, the evidence of a neuroimmune regulation of the circadian system and its disturbance with aging, highlights the importance of proinflammatory cytokines in this complex cross-talk. The biological rhythms disruption with age and some diseases (jet lag, cancer and seasonal affective disorder), could contribute increasing the immune system impairment and consequently the loss of health.

According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the agerelated impairment of organism functions, including those of the nervous and immune systems, as well as of the neuroimmune communication, which explains the altered homeostasis and the resulting increase of morbidity and mortality. Overproduction of oxidant compounds can induce an inflammatory response, since oxidants are inflammation effectors. Thus, oxidation and inflammation are interlinked processes and have many feedback loops. However, the nature of their potential interactions, mainly in the brain and immune cells, and their key involvement in aging remain unclear. Moreover, in the context of the neuroimmune communication, it has been described that an oxidative-inflammatory situation occurs in subjects with anxiety, and this situation contributes to an immunosenescence, alteration of survival responses and shorter life span. As an example of this, a model of premature aging in mice, in which animals show a poor response to stress and high levels of anxiety, an oxidative stress in their immune cells and tissues, as well as a premature immunosenescence and a shorter life expectancy, will be commented in the present review. This model supports the hypothesis that anxiety can be a situation of chronic oxidative stress and inflammation, especially in brain and immune cells, and this accelerates the rate of aging.

Nitric oxide (NO) has an important role in physiological and pathological processes in general, and in particular plays a homeostatic role in the nervous and immune systems. The many different physiological functions of NO include those of a mediator of blood vessel dilation, neurotransmitter, neuromodulator and inductor of mitochondrial biogenesis. In addition, NO can transform into highly reactive and harmful molecules producing an impairment of the DNA, lipids or proteins, and thus altering their function. This dual action of NO, by which it plays an important role in homeostasis and aids the development of pathological processes, makes this molecule an interesting target for medical therapies, especially with respect to the nervous and immune systems. This review describes the multiple roles of NO played out in the nervous and immune systems during different physiological and pathophysiological processes.

Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the ‘70s, it was demonstrated that the production and secretion of thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of thymulin and should also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models and eventually, in humans.

A few years ago the endocannabinoid system has been recognized as a major neuromodulatory system whose main functions are to exert and maintain the body homeostasis. Several different endocannabinoids are synthesized in a broad class of cell types, including those in the brain and the immune system; they bind to cannabinoid G-protein-coupled receptors, having profound effects on a variety of behavioral, neuroendocrine and autonomic functions. The coordinated neural, immune, behavioral and endocrine responses to inflammation are orchestrated to provide an important defense against infections and help homeostasis restoration in the body. These responses are executed and controlled mainly by the hypothalamic-pituitary adrenal axis. Also, the hypothalamic-neurohypophyseal system is essential for survival and plays a role recovering the homeostasis under a variety of stress conditions, including inflammation and infection. Since the endocannabinoid system components are present at sites involved in the hypothalamic-pituitary axis regulation, several studies were performed in order to investigate the endocannabinoid-mediated neurotransmitters and hormones secretion under physiological and pathological conditions. In the present review we focused on the endocannabinoids actions on the neuroendocrine response to inflammation and infection. We provide a detailed overview of the current understanding of the role of the endocannabinoid system in the recovering of homeostasis as well as potential pharmacological therapies based on the manipulation of endocannabinoid system components that could provide novel treatments for a wide range of disorders.

The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) Alzheimer's disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. Neuroimmune regulatory proteins (NIReg) such as CD95L, CD200, CD47, sialic acid, complement regulatory proteins (CD55, CD46, fH, C3a), HMGB1, may control the adverse immune responses in health and diseases. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury as well as an adverse inflammatory response in acute and chronic settings. We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler’s virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.

The crosstalk in the functional interplay of the neuroimmune system is essential to ensure homeostasis preservation and health. Alzheimer’s disease (AD) can be understood in the context of aging of this neuroimmune communication. AD has an important genderdependent component and is benefitted by lifestyle strategies such as physical exercise, enriched environments and nutrition. Recently, the functional and redox state of peripheral immune cells has been proposed as a useful tool for measuring the progression of AD. The present review summarizes the relevance of the disruption of crosstalk among neurons, glial cells, immune mediators and cells from the very beginning of the prodromal stages of AD, when early BPSD symptoms have already started but cognitive function still seems apparently normal. The study of the role of neuroimmune system and how its disruption contributes to the onset of disease may help in understanding its biological mechanisms and in finding behavioral parameters and immunological biomarkers for the prodromic phases. Here we present results of 3xTg-AD mice from pre-morbid to early-stages of AD and how early BPSD-like symptoms correlate with changes in the organometrics of thymus and spleen that are indirect indicators of the immunological status. These functional relationships between behavioral and peripheral system also revealed the existence of differences between biological and chronological ages (an advanced biological age) since the prodromal stages. Overall, the data available suggest that the crosstalk between behavior (nervous) and immune system plays an important role since prodromal stages of AD.

Pleiotropic effects, great potency, and the capacity to induce its own production are distinguishing characteristics of IL-1. Among the multiple physiological effects of this cytokine, we emphasize here its role in supporting immune processes by stimulating most immune cells, and in re-setting glucose homeostasis. These aspects are complementary because stimulatory actions of IL-1 may be due to its capacity to increase glucose uptake by immune cells in the periphery and to affect the control of glucose homeostasis at brain levels, so as to deviate this main fuel to immune cells during inflammatory and infectious diseases. Thus, IL-1 can contribute to maintain a lean phenotype, inhibit food intake, and exert hypoglycemic effects. However, these effects of IL-1 can be overridden particularly when it is overproduced ectopically in other tissues, as it occurs during the autoimmune process that destroys the pancreas and causes type 1 diabetes, or when obesity triggers its production in adipose tissue and influences the development of type 2 diabetes. During obesity, products of enlarged adipocytes, e.g. fatty acids, are sensed as danger signals by infiltrating immune cells and, together with hypoxia, results in an ectopic overproduction of IL-1 that is largely mediated by activation of the NLRP3-caspase-1 inflammasome. Insulin and leptin resistance develops by mutual IL-1β-TNFα induction, and hyperglycemia causes ectopic production of IL-1 in the pancreas, which deregulates insulin production and favors the development of type 2 diabetes. In conclusion, whether IL-1 exerts physiologic or pathologic effects depends on its amount and on the spatial and temporal pattern of its production.

Preterm birth is the leading cause of perinatal morbidity and mortality. Pathological processes that have been linked with preterm birth infection and / or intrauterine inflammation are most frequently found associated with their induction. Studies in animal models and human research showed prior infections to the induction of labor, the anteriority of infection over labor induction, and the existence of a subclinical latency phase between these two phenomena. The ascending route from the vagina and the cervix is preponderant but also microorganisms may access the amniotic cavity and the fetus by other pathways. During inflammation associated to infection, Prostaglandins are released simultaneously with Nitric oxide and their overproduction could be detrimental. Prostaglandins promote uterine contractions contributing to embryonic and fetal expulsion. Therefore aberrant activation of the inflammatory response may cause premature labor and this does not seem to depend on how the microoorganisms accessed the uterus.

Periodontitis is a chronic inflammatory complex disease caused by microorganisms. It may be influenced by diverse systemic disorders, environmental, genetic and socio-psychological factors with the ability to alter the balance of the host neuro-immunoendocrine responses. It is characterized by the progressive destruction of the tooth supporting apparatus leading to tooth loss, with possible impact on general health. Starting with a brief description of the periodontium, etiopathogenesis, repair processes and several physiological mechanisms and their disarray on periodontium response to bacterial challenge. Following, the negative effects of stress on the disease and some remarks on the recently discovered effects of oxytocin that modulate stress response and its role in individual coping mechanisms to stress. We also focus on the participation of components and functions of endocannabinoid system with anti-inflammatory actions on gingiva. Finally, a discussion that may link between diabetes, cardiovascular diseases, stroke and metabolic syndrome associated with periodontal disease; all of them sharing a common denominator that is inflammation and oxidative stress.

Sjogren’s syndrome (SS) is a chronic inflammatory disease characterized by salivary and lacrimal gland dysfunction although extraglandular manifestations are also found. Suitable study models and in vitro cell culture designs are used to approach SS pathogenic mechanisms. Cellular and molecular pathways involved in gland homeostasis loss and the autoimmune response are focused in the search of novel drug targets and biomarkers. Vasoactive intestinal peptide (VIP) has trophic, pro-secretory and immunomodulatory effects in several chronic and autoimmune disease models. Here we review evidence pointing to its role as an endogenous modulator of gland homeostasis at early stages of the disease. Particularly, mechanisms involving VIP/VPAC system in the course of salivary function impairment in the non obese diabetic (NOD) mouse model of Sjögren’s syndrome are described.

Crohn’s disease and ulcerative colitis are the major inflammatory bowel diseases (IBD) in humans. With the incidence of increasing world-wide, it currently affects 4 million people in Europe and in the USA. It is an idiopathic, chronic relapsing intestinal disorder of complex pathogenesis. The etiology of both diseases remains unknown, but recent data suggest that they appear in genetically predisposed individuals, because of an exaggerated mucosal immune response to commensal microbiota present in the gut. There is increasing evidence for an alteration of the immune regulation mechanisms in patients, with mucosal T lymphocytes playing a crucial role in the pathogenic events leading to tissue damage. It is clear that the disease is the result of environmental factors acting on genetically predisposed individuals. In humans, psychological trauma, stress or depression, have been involved as precipitating or relapsing factors of the disease, although this link remains elusive. However, several published works using colitis animal models subjected to stress conditions, have given consistent proof as to the molecular link between emotional stress, increase in epithelial permeability, alteration of the gut microflora composition and activation of pre-sensitized T lymphocytes. Gaining knowledge of the cross talk between components of the brain – gut – immune system axis may be fruitful in the design of future therapeutic approaches, such as the use of vasointestinal peptide (VIP) in this pathology.

By focusing on the studies of primate behaviour and human neuroscience, we describe how different neurological processes are the base of proximate aspects of social-decision making. We also review the fact that distinct aspects of animal behaviour are not under conscious or abstract control and that instead they may be regulated by adaptive ´rules of thumb´. In particular, by describing the microbiota- gut-brain axis we elaborate on suggesting that microbiota has an influence on within-individual aspects of social decision making and in particular facilitating social interactions. Finally, we present comparative evidence of the role of microorganisms as modifiers of aspects of kinship, reproduction and group-members´ recognition, suggesting how microbiota also has an influence on betweenindividual aspects of decision making, which are themselves primary aspects of cooperation. In summary, we propose that modern socioeconomic choice theories may still benefit from alternative theoretical frameworks that consider the human being as a complex organism, with intrinsic constraints and capacities product of its evolutionary history, and not just as an exclusively-cognitive decision maker acting independently of its closest partners and commensals: its microbiota.