Effect Of Immune System Activation Research Articles

Experimental immune challenges reduce the quality of male antennae and female pheromone output

Sexual signalling is a key feature of reproductive investment, yet the effects of immune system activation on investment into chemical signalling, and especially signal receiver traits such as antennae, are poorly understood. We explore how upregulation of juvenile immunity affects male antennal functional morphology and female pheromone attractiveness in the gumleaf skeletonizer moth, Uraba lugens. We injected final-instar larvae with a high or low dose of an immune elicitor or a control solution and measured male antennal morphological traits, gonad investment and female pheromone attractiveness. Immune activation affected male and female signalling investment: immune challenged males had a lower density of antennal sensilla, and the pheromone of immune-challenged females was less attractive to males than their unchallenged counterparts. Immune challenge affected female investment into ovary development but not in a linear, dose-dependent manner. While there was no effect of immune challenge on testes size, there was a trade-off between male pre- and post-copulatory investment: male antennal length was negatively correlated with testes size. Our study highlights the costs of elaborate antennae and pheromone production and demonstrates the capacity for honest signalling in species where the costs of pheromone production were presumed to be trivial.

Early Inflammation Dysregulates Neuronal Circuit Formation In Vivo via Upregulation of IL-1β.

Neuroimmune interaction during development is strongly implicated in the pathogenesis of neurodevelopmental disorders, but the mechanisms that cause neuronal circuit dysregulation are not well understood. We performed in vivo imaging of the developing retinotectal system in the larval zebrafish to characterize the effects of immune system activation on refinement of an archetypal sensory processing circuit. Acute inflammatory insult induced hyperdynamic remodeling of developing retinal axons in larval fish and increased axon arbor elaboration over days. Using calcium imaging in GCaMP6s transgenic fish, we showed that these morphologic changes were accompanied by a shift toward decreased visual acuity in tectal cells. This finding was supported by poorer performance in a visually guided behavioral task. We further found that the pro-inflammatory cytokine, interleukin-1β (IL-1β), is upregulated by the inflammatory insult, and that downregulation of IL-1β abrogated the effects of inflammation on axonal dynamics and growth. Moreover, baseline branching of the retinal ganglion cell arbors in IL-1β morphant animals was significantly different from that in control larvae, and their performance in a predation assay was impaired, indicating a role for this cytokine in normal neuronal development. This work establishes a simple and powerful non-mammalian model of developmental immune activation and demonstrates a role for IL-1β in mediating the pathologic effects of inflammation on neuronal circuit development.SIGNIFICANCE STATEMENT Maternal immune activation can increase the risk of neurodevelopmental disorders in offspring; however, the mechanisms involved are not fully understood. Using a non-mammalian vertebrate model of developmental immune activation, we show that even brief activation of inflammatory pathways has immediate and long-term effects on the arborization of axons, and that these morphologic changes have functional and behavioral consequences. Finally, we show that the pro-inflammatory cytokine IL-1β plays an essential role in both the effects of inflammation on circuit formation and normal axonal development. Our data add to a growing body of evidence supporting epidemiological studies linking immune activation to neurodevelopmental disorders, and help shed light on the molecular and cellular processes that contribute to the etiology of these disorders.

TNFα-dependent anhedonia and upregulation of hippocampal serotonin transporter activity in a mouse model of collagen-induced arthritis

The serotonin transporter (SERT) facilitates high affinity reuptake of 5-HT from the extracellular fluid and dysregulation of transporter function has been implicated in a range of mood disorders including depression. Recent studies have linked immune system activation to depression as well as to altered serotonin transporter activity. Advancing previous studies, which have mainly focussed on acute effects of immune system activation, in this study we used collagen-induced arthritis (CIA) in mice as a model of chronic inflammatory disease, to investigate the effect of prolonged inflammation on brain SERT function and behaviour. We found that 5–6 weeks after immunisation, CIA mice display anhedonia, a core depression-like behaviour. Behavioural symptoms are temporally correlated with a region-specific upregulation of SERT activity in the hippocampus, which occurs at a post-translational level and is independent of SERT trafficking. Kinetic analysis of 5-HT uptake revealed that the elevation of transporter activity is due to an increase in 5-HT transport capacity (Vmax) with no change in apparent Km values, suggesting that different regulatory mechanisms govern SERT modulation under chronic versus acute inflammatory conditions. Protein expression of tumour necrosis factor receptor 1 (TNFR1) was specifically upregulated in the hippocampus of CIA mice, indicating altered TNFα signalling. Anti-TNFα treatment using etanercept not only diminished joint inflammation, but also prevented the development of anhedonia and the upregulation of SERT activity in the hippocampus, suggesting a key role for TNFα signalling in brain function regulation in this disease model. Our study provides novel insight into molecular mechanisms underlying mood symptoms in chronic inflammatory diseases, with particular relevance to rheumatoid arthritis.

Characterization of sleep-pattern and neuro-immune-endocrine markers at 24 hour post-injection of a single low dose of lipopolysaccharide in male Wistar rats

The long-term effect of immune system activation by a low dose of lipopolysaccharide on neuro-immune-endocrine regulation is unclear. Sleep, neurotransmitter concentrations, TNF-α, and corticosterone levels were evaluated in male Wistar rats implanted with conventional sleep recordings. In this work, we found that REM sleep was reduced in the first 4 h post-injection, without affecting the total sleep time, while adrenaline concentration was reduced in the hippocampus at 24 h post-injection of LPS. Our results demonstrated that, although the acute immune response was not evident 24 h after the injection of LPS, it was able to promote the reduction of AD in the hippocampus, which may explain in part the depressive behavior reported in rodents following LPS administration.

Induced lung inflammation and dietary protein supply affect nitrogen retention and amino acid metabolism in growing pigs.

It is hypothesised that during immune system activation, there is a competition for amino acids (AA) between body protein deposition and immune system functioning. The aim of the present study was to quantify the effect of immune system activation on N retention and AA metabolism in growing pigs, depending on dietary protein supply. A total of sixteen barrows received an adequate (Ad) or restricted (Res) amount of dietary protein, and were challenged at day 0 with intravenous complete Freund's adjuvant (CFA). At days -5, 3 and 8, an irreversible loss rate (ILR) of eight AA was determined. CFA successfully activated the immune system, as indicated by a 2- to 4-fold increase in serum concentrations of acute-phase proteins (APP). Pre-challenge C-reactive protein concentrations were lower (P<0·05) and pre- and post-challenge albumin tended to be lower in Res-pigs. These findings indicate that a restricted protein supply can limit the acute-phase response. CFA increased urinary N losses (P=0·04) and tended to reduce N retention in Ad-pigs, but not in Res-pigs (P=0·07). The ILR for Val was lower (P=0·05) at day 8 than at day 3 in the post-challenge period. The ILR of most AA, except for Trp, were strongly affected by dietary protein supply and positively correlated with N retention. The correlations between the ILR and APP indices were absent or negative, indicating that changes in AA utilisation for APP synthesis were either not substantial or more likely outweighed by a decrease in muscle protein synthesis during immune system activation in growing pigs.

Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation.

Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus.

Is immune system activation/systemic inflammation a prerequesite for successful reproduction? association of immune system activation with embryo quality during in vitro fertilization (IVF)

Requiring implantation and tolerance of semi-allograft, pregnancy mandates complex immunological processes. Degree of immune system activation has been associated with pregnancy complications. Effects of immune system activation on embryo quality has, however, never been investigated. Cohort study. 125 infertile women underwent 169 IVF cycles. Embryo quality was defined as good (4-cell d-2; 8-cell d-3, Grade 4-5), poor (arrested or degenerated, Grade ≤ 2) or fair (all embryos in between). Immune system activation was tested utilizing immune parameters, demonstrated effective in prior studies in identifying immune system activation with good sensitivity: thyroid antibodies (peroxidase, thyroglobulin, thyroid receptor antibodies), total immunoglobulins (IgG, IgM, IgA, IgE), antiphospholipid antibodies (β2 glycoprotein, anticardiolipin, antiphosphatidylserine, lupus anticoagulant), antinuclear antibody, anti-adrenal antibody (21-hydroxylase) and anti-ovarian antibodies. Any positive finding was considered indicative of immune activation. Patient age was 38.9 ± 5.5 years. Immune system activation was associated with significantly better embryo quality (P=0.008). This association persisted after adjustment for age and repeat IVF cycles (P=0.006). Observed improvement in embryo quality derived mostly from better embryo grade (3.7 ± 0.05 vs. 3.4 ± 0.07, P=0.002). This is the first report associating improved embryo quality with maternal immune system activation. These data relate to recent report from our center that normal androgen levels appear associated with immune system activation, while low androgen levels fail to show such activation (Gleicher et al ESHRE 2013/Reprod Biol Encocrinol 2013; In press). Combined, these data suggest that immune system activation/systemic inflammation, possibly via androgen effects on follicle maturation, contributes to embryo quality and pregnancy success with IVF.

Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1β administration

Activation of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers resistant to radiotherapy. Cytokine-based treatments induce a range of “sickness” behaviors (e.g. depression, anxiety, pain, anorexia, and fatigue). Activation of the hypothalamic pituitary-adrenal axis via the induction of corticotropin releasing factor (CRF) may underlie these unwanted side effects. This study used repeated systemic injections of the pro-inflammatory cytokine interleukin-1β (IL-1β) to model the sickness behaviors and biochemical effects of immune system activation. We assessed the ability of CRF type I receptor (CRF1) antagonism to reduce biochemical and behavioral signs of sickness induced by IL-1β treatment. Forty Wistar rats were assigned to one of four groups: 1) saline+vehicle; 2) saline+DMP904 (CRF1 antagonist); 3) IL-1β+vehicle; 4) IL-1β+DMP904. Rats received intraperitoneal injections of either DMP904 or vehicle and of IL-1β or saline for six days. Sickness behavior was evaluated using body weight assessments and forced swim testing (FST). Blood and brain samples were collected to measure cytokine, p38 mitogen-activated protein kinase (MAPK), and phospho-p38 MAPK levels using multiplex techniques. There were significant reductions in body weights and FST immobility times associated with IL-1β administration. Rats administered IL-1β had significantly higher serum levels of IL-10, but not interferon-γ. Within the hippocampus, IL-1β reduced levels of p38 MAPK, but had no impact on levels of phospho-p38 MAPK except in the presence of DMP904. When administered alone, DMP904 had no significant effect on p38 MAPK or phospho-p38 MAPK in the hippocampus, but when given with IL-1β led to increased phosphorylation of p38 MAPK. IL-1β and DMP904 reduced levels of p38 MAPK within the hypothalamus, while co-administration of IL-1β and DMP904 abolished the effects of either drug alone. IL-1β decreased immobility time in the FST, and led to reductions in body weight, changes in serum cytokine levels and p38 MAPK regulation within the hippocampus and hypothalamus. DMP904 blocked some of the neurochemical effects of IL-1β, but did not impact the behavioral measures, or serum cytokines. Thus, additional studies will be needed to determine whether CRF1 antagonism is an effective treatment for cytokine-induced sickness.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Molecular Basis of Inflammation: Relationships Between Catabolic Cytokines, Hormones, Energy Balance, and Muscle

Inflammation alters energy metabolism, macro- and micronutrient balances, and body composition. This review briefly describes the current understanding of how this happens, focusing on the effect of immune system activation on energy balance. Conversely, malnutrition also has a large impact on immune function, with both undernutrition (causing immune suppression) and overnutrition (causing inflammation) now well described. Improved understanding of the interplay of the immune system and metabolism can lead to new treatments for both cachexia and obesity.

Neonatal immune challenge does not affect body weight regulation in rats

The perinatal environment plays a crucial role in programming many aspects of adult physiology. Myriad stressors during pregnancy, from maternal immune challenge to nutritional deficiency, can alter long-term body weight set points of the offspring. In light of the increasing concern over body weight issues, such as obesity and anorexia, in modern societies and accumulating evidence that developmental stressors have long-lasting effects on other aspects of physiology (e.g., fever, pain), we explored the role of immune system activation during neonatal development and its impact on body weight regulation in adulthood. Here we present a thorough evaluation of the effects of immune system activation (LPS, 100 microg/kg ip) at postnatal days 3, 7, or 14 on long-term body weight, adiposity, and body weight regulation after a further LPS injection (50 microg/kg ip) or fasting and basal and LPS-induced circulating levels of the appetite-regulating proinflammatory cytokine leptin. We show that neonatal exposure to LPS at various times during the neonatal period has no long-term effects on growth, body weight, or adiposity. We also observed no effects on body weight regulation in response to a short fasting period or a further exposure to LPS. Despite reductions in circulating leptin levels in response to LPS during the neonatal period, no long-term effects on leptin were seen. These results convincingly demonstrate that adult body weight and weight regulation are, unlike many other aspects of adult physiology, resistant to programming by a febrile-dose neonatal immune challenge.

Lipopolysaccharide and interleukin-1β decrease sucrose intake but do not affect expression of place preference in rats

Immune system activation has been shown to induce decreased interest in pleasurable stimuli. Studies of this phenomenon have assessed the effect of cytokines or lipopolysaccharide (LPS) on behavior maintained by primary reinforcers, stimuli, such as palatable solutions, that effectively reinforce behavior without prior training. The studies reported in this paper replicated findings of immune system activation decreasing intake of a palatable solution and assessed the effects of immune activation on behavior maintained by a conditioned reinforcer, a stimulus paired with a the palatable solution. Using a conditioned place preference procedure, the effects of LPS and interleukin-1β (IL-1β) on sucrose intake (primary reinforcer) and preference for a sucrose-paired environment (conditioned reinforcer) were tested. LPS and IL-1β decreased sucrose intake but had no effect on the expression of a sucrose-induced place preference, indicating a differential effect of immune system activation on appetitive behaviors maintained by primary and conditioned reinforcers. Finally, it was shown that a sucrose-induced place preference is sensitive to the motivational state of the subjects at the time of testing; a sucrose-induced place preference was demonstrated if rats were tested when water deprived but not if tested after free access to water.

Overview of the Immune Dynamics of the Digestive System

The digestive tract of the chicken is a major site of pathogen exposure. Although the bird has a multifaceted set of tools to prevent or resist infection, any activation of the immune system can divert nutrients away from production. Therefore, prevention of pathogenic exposure is preferred. However, it is unlikely that the bird can escape exposure to all pathogens during its life, thus the ability to respond to immunologic challenges is essential. The immune system of birds is similar to that of mammals in terms of structure and function, although some differences do exist, particularly in regulatory aspects. The innate immune system responds nonspecifically to foreign molecules and is essential for the induction of the specific (acquired) immune response. Cells of the innate immune system include macrophages, dendritic cells, heterophils, and natural killer cells. The acquired immune response involves recognition of a specific antigen and response by lymphocytes. Cytotoxic T lymphocytes are especially effective at inducing cells infected with intracellular pathogens to undergo apoptosis. Helper T lymphocytes increase the effectiveness of innate immune cells in combating extracellular pathogens and are also essential for activating B lymphocytes, which produce antibodies specific to the invading pathogen. All aspects of the immune system function together, although one aspect will often dominate, depending on the type and severity of the infection. This paper reviews the basics of avian immune function in general and discusses the immune system in the digestive tract in particular in birds. The consequences of activation of the immune system are presented.Currently, growth-promoting antibiotics are not used in poultry in many countries; the North American industry may be moving in that direction as well, either through legislation or consumer pressure. Several nonantibiotic means of manipulating the immune system to prevent the health- and performance-suppressing effects of immune system activation are presented here.

Behavioral and Motivational Effects of Immune-System Activation

Immune-system activity induces changes in animal behavior such as decreased food intake, decreased exploratory behavior, increased sleep, and impaired cognitive functioning. These changes are mediated by proinflammatory cytokines, and the administration of cytokines produces the same profile of behavior change as do infection and inflammation. Results demonstrating differential effects of immune-system activation depending on environmental contingencies and physiological states support the hypothesis that the behavioral effects of immune activity may be mediated by motivation. In this article, the author outlines the behavioral changes induced by immune-system activation and discusses evidence for a motivational analysis of immune-induced behavior change and the potential involvement of motivation in human sickness behavior.