Search

Simple Summary: Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with reduced immune protection against chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with immune system dysfunction induced by chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. This study involved a search of scientific literature covering the neuroendocrine, cellular, and molecular mechanisms of stress-induced immunosuppression regulation, as well as modern methods for its diagnosis. Major international bibliographic databases covering publications in biomedicine, psychophysiology, and immunology were selected for the search. The results of the analysis identified key mechanisms regulating stress-induced immunosuppression. The reviewed publications provided detailed descriptions of the neuroendocrine and cytokine processes underlying immune response suppression under stress. A significant portion of the data confirms that the activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequent elevation of cortisol levels exert substantial immunosuppressive effects on immune cells, particularly macrophages and lymphocytes, leading to the suppression of innate and adaptive immune responses. The data also highlight the crucial role of cortisol and catecholamines (adrenaline and noradrenaline) in initiating immunosuppressive mechanisms under chronic stress. [ABSTRACT FROM AUTHOR]

Simple Summary: Adipose tissue (AT) plays an important role in maintaining lipid homeostasis and regulating immune function in mammals. However, the regulatory functions and mechanisms of avian AT in immune response have not been reported. In this study, we found that chicken AT actively responded to stress-induced immunosuppression (SIIS), and adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1A (CPT1A), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) all constitute the key genes involved in the processes of SIIS inhibiting the immune response to the Newcastle disease virus vaccine. Moreover, SIIS significantly inhibited the different phases of the primary and secondary immune response in AT through the upregulation of steroid anabolism. Interestingly, AT could inhibit or promote immune responses through the upregulation or downregulation of steroid metabolism, respectively. The miR-29a/c-3p-HMGCR network is a potential regulation mechanism of AT participating in immune response and circulating miR-29a/c-3p is a potential molecular marker. This study can provide references for further investigating the immune functions of AT. Lipid metabolism plays an important role in maintaining lipid homeostasis and regulating immune functions. However, the regulations and mechanisms of lipid metabolism on the regional immune function of avian adipose tissue (AT) have not been reported. In this study, qRT-PCR was used to investigate the changes and relationships of different lipid metabolism pathways in chicken AT during stress-induced immunosuppression (SIIS) inhibiting immune response to Newcastle disease virus vaccine, then the miRNA regulation patterns of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene and its potential applications were further identified. The results showed that AT actively responded to SIIS, and ATGL, CPT1A and HMGCR were all the key genes involved in the processes of SIIS inhibiting the immune responses. SIIS significantly inhibited the natural and specific immune phases of the primary immune response and the initiation phase of the secondary immune response in AT by suppressing T cells by up-regulating steroid anabolism. Moreover, steroid metabolism could play dual roles in regulating the regional immune functions of AT. The miR-29a/c-3p-HMGCR network was a potential regulation mechanism of steroid metabolism in AT, and serum circulating miR-29a/c-3p had the potential as molecular markers. The study can provide valuable references for an in-depth investigation of the regional immune functions regulated by lipid metabolism in AT. [ABSTRACT FROM AUTHOR]

ABSTRACT: Stress-induced immunosuppression (SIIS) is one of the common problems in intensive poultry production, which often reduces the prevention and control effects of various vaccines, including infectious bursal disease virus (IBDV) vaccine, and brings enormous economic losses to the poultry industry. However, the molecular mechanisms of SIIS inhibiting immune response to IBDV vaccine remain unclear. In this study, suppressor of cytokine signaling 3 (SOCS3) gene was selected and stress-induced immunosuppressed chickens were simulated using dexamethasone (Dex). Quantitative real-time PCR (qRT-PCR) was conducted to analyze its expression characteristics and game relationships between SOCS3 gene and miR-27b-3p (it could target SOCS3 gene) in the process of SIIS inhibiting immune response to IBDV vaccine in chicken, and the potential application value of circulating miR-27b-3p as a biomarker was also identified. The results showed that SOCS3 gene and miR-27b-3p were significantly differentially expressed in the candidate tissues during SIIS inhibiting the immune response to IBDV (P < 0.05), respectively, which were key factors involved in the process. Moreover, miR-27b-3p and SOCS3 gene showed game regulation relationships in several tissues during the process, so the miR-27b-3p/SOCS3 regulatory network was one of the key mechanisms of SOCS3 gene participating in the process. Circulating miR-27b-3p was differentially expressed in serum at 10 time points (1, 2, 3, 4, 5, 7, 14, 21, 28, and 35 days postimmunization (dpi)) in the process (P < 0.05), showing that circulating miR-27b-3p was a valid candidate target as a molecular marker for detecting SIIS inhibiting the IBDV immune response. This study can provide references for further studying molecular mechanisms of stress affecting immune response.

MiR-155 and CTLA-4 are important factors involved in the regulation of immune function. However, there is no report about their involvement in function regulation of stress-induced immunosuppression affecting immune response. In this study, the chicken model of stress-induced immunosuppression affecting immune response (simulation with dexamethasone and immunization with Newcastle disease virus (NDV) attenuated vaccine) was established, then the expression characteristics of miR-155 and CTLA-4 gene were analyzed at several key time points during the processes of stress-induced immunosuppression affecting NDV vaccine immune response at serum and tissue levels. The results showed that miR-155 and CTLA-4 were the key factors involved in stress-induced immunosuppression and NDV immune response, whose functions involved in the regulation of immune function were different in different tissues and time points, and 2 day post immunization (dpi), 5dpi and 21dpi were the possible key regulatory time points. CTLA-4, the target gene of miR-155, had significant game regulation relationships between them in various tissues, such as bursa of Fabricius, thymus and liver, indicating that miR-155-CTLA-4 pathway was one of the main mechanisms of their involvement in the regulations of stress-induced immunosuppression affecting NDV immune response. This study can lay the foundation for in-depth exploration of miR-155-CTLA-4 pathway involved in the regulation of immune function. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating miRNAs play important roles in immune response and stress-induced immunosuppression, but the function and mechanism of stress-induced immunosuppression affecting the NDV vaccine immune response remain unknown. In our study, key timepoints, functions, mechanisms, and potential biomarkers of circulating miRNAs involved in immune response and immunosuppression were discovered, providing a theoretical basis for studying the roles of circulating miRNAs in immune regulation. Studies have shown that circulating microRNAs (miRNAs) are important players in the immune response and stress-induced immunosuppression. However, the function and mechanism of stress-induced immunosuppression affecting the immune response to the Newcastle disease virus (NDV) vaccine remain largely unknown. This study analyzed the changes of 15 NDV-related circulating miRNAs at different immune stages by qRT-PCR, aiming to explore the key timepoints, potential biomarkers, and mechanisms for the functional regulation of candidate circulating miRNAs under immunosuppressed conditions. The results showed that stress-induced immunosuppression induced differential expressions of the candidate circulating miRNAs, especially at 2 days post immunization (dpi), 14 dpi, and 28 dpi. In addition, stress-induced immunosuppression significantly affected the immune response to NDV vaccine, which was manifested by significant changes in candidate circulating miRNAs at 2 dpi, 5 dpi, and 21 dpi. The featured expressions of candidate circulating miRNAs indicated their potential application as biomarkers in immunity and immunosuppression. Bioinformatics analysis revealed that the candidate circulating miRNAs possibly regulated immune function through key targeted genes, such as Mg2+/Mn2+-dependent 1A (PPM1A) and Nemo-like kinase (NLK), in the MAPK signaling pathway. This study provides a theoretical reference for studying the function and mechanism of circulating miRNAs in immune regulation. [ABSTRACT FROM AUTHOR]

• "CircMYO1B/miR-155" is a common mechanism for SIIS affecting immunities. • 5 dpi and heart, proventriculus are the key time point and tissues, respectively. • MAPK signaling pathway plays a key regulatory role in SIIS affecting immunities. Stress-induced immunosuppression (SIIS) can weaken the immune response effect of poultry vaccination, and bring huge hidden dangers and economic losses to the poultry industry. However, the detailed molecular mechanisms are still not fully understood. Unveiling the common mechanism of SIIS affecting the immune response to different vaccines is critical for detecting and minimizing the losses caused by SIIS. This study used glucocorticoid dexamethasone (Dex) to simulate SIIS, and three classic avian vaccines (including avian influenza virus (AIV), Newcastle disease virus (NDV), and infectious bursal disease virus (IBDV)) were used to induce immune responses in chicken. Quantitative real-time PCR (qRT-PCR) revealed the expression characteristics and functions of circMYO1B and miR-155 in the processes of SIIS affecting the immune response to the aforementioned avian vaccines, as well as their targeted regulatory relationship. Subsequent bioinformatics analysis predicted FOS, one of the potential target genes of miR-155. The results showed that circMYO1B/miR-155 pathway served as a key common mechanism by which SIIS affected the immune response to the three vaccines. Both heart and proventriculus appeared to be the crucial tissues for this process, with five days post immunization (dpi) emerging as the primary time of interest. Moreover, mitogen-activated protein kinase (MAPK) signaling system played a key role in modulating the immune response subsequent to SIIS administration. Our findings provide new insights into the immune function of competitive endogenous RNA (ceRNA), which have important function in the detection and treatment of SIIS affecting vaccine immunity. [ABSTRACT FROM AUTHOR]

Highlights • Mitotane treatment temporarily suppressed corticosterone levels. • Corticosterone treatment suppressed complement and bactericidal activity. • Corticosterone levels did not affect natural antibody activity. Abstract Stress-induced inhibition of innate immune activity has been observed in a variety of wild birds and may increase chances of infection because this activity constitutes the first line of defense against pathogens. We previously reported that the transient elevation of plasma corticosterone (CORT; the primary avian glucocorticoid) that occurs during stress is necessary for stress-induced suppression of natural antibody-mediated, complement-mediated, and bactericidal activity. Here, we further investigated the regulatory role of CORT during this suppression. To this end, we treated House Sparrows (Passer domesticus) with mitotane to block endogenous CORT production, administered CORT at one of three doses (HI: 1.34 mg/kg; LO: 1.00 mg/kg; CON: vehicle), and assessed natural antibody-mediated, complement-mediated, and bactericidal activity during acute stress induced by handling and restraint. Mitotane administration eliminated the endogenous plasma CORT increase that normally takes place during stress, and corticosterone treatment increased plasma CORT to levels similar to those measured in intact birds during acute stress. As predicted, mitotane-treated birds receiving CON injections did not exhibit stress-induced suppression of complement-mediated and bactericidal activity, and CORT administration at both LO and HI doses restored this suppression. Contrary to expectations, mitotane-treated birds receiving CON injections demonstrated stress-induced suppression of natural antibody-mediated activity. Furthermore, CORT administration did not influence this parameter. These results suggest that stress inhibits innate immune activity through both CORT-dependent and CORT-independent mechanisms, but the contribution of these mechanisms can vary. This variation may result from effects of environmental factors, the identity and role of which warrant further research. [ABSTRACT FROM AUTHOR]

At present, stress-induced immunosuppression is still a hidden threat that leads to immunization failure and outbreaks of poultry diseases, and causes huge economic losses to the modern poultry industry. However, the molecular mechanisms of stress-induced immunosuppression affecting viral vaccine immunity are still poorly understood. Here, we identified circAKIRIN2 as a conserved circular transcript in chicken, and explored its expression patterns in different immune states by quantitative real-time PCR (qRT-PCR), then conducted bioinformatics analysis. The results showed that circAKIRIN2 actively participated in the process of stress-induced immunosuppression affecting the immune response to infectious bursal disease virus (IBDV) vaccine. The key time points for circAKIRIN2 involving in the process were 2 day post immunization (dpi), 5 dpi, and 28 dpi, especially at the acquired immune stage. The important tissues that responded to the process included the heart, liver, and lung, all of which changed significantly. In addition, circAKIRIN2 as a competing endogenous RNA (ceRNA) sponging zinc finger and BTB domain containing 20 (ZBTB20) was a potential molecular mechanism for regulating immune functions in the process. In conclusion, circAKIRIN2 is a key regulatory factor for stress-induced immunosuppression affecting the IBDV vaccine immune response, and this study can provide a new perspective for exploring the molecular regulatory mechanisms of stress-induced immunosuppression affecting immune response. • Stress-induced immunosuppression affects IBDV immune response via circAKIRIN2. • CircAKIRIN2 is a key regulatory factor mainly involved in acquired immunity. • CircAKIRIN2 sponging ZBTB20 is the potential key mechanism. [ABSTRACT FROM AUTHOR]

Stress-induced effects on innate immune activity in wild birds have been difficult to predict. These difficulties may arise from the frequent assumptions that (1) the stress response influences different components of the immune response similarly, (2) stress-induced effects do not change over the course of the stress response and (3) glucocorticoids are the primary regulators of stress-induced changes of immune activity. We tested the first two assumptions by measuring three components of innate immunity at two times during the stress response in captive adult male house sparrows, Passer domesticus. Acute stress resulting from handling and restraint suppressed plasma lytic and microbicidal activity within 10 min and reduced plasma agglutination ability within 120 min. We tested the third assumption by measuring stress-induced effects in sparrows that were pharmacologically adrenalectomized by mitotane administration. Confirming the effectiveness of this treatment, mitotane-treated birds had lower pre-stress plasma CORT than control birds and showed no increase in plasma CORT during acute stress. The innate immune activity of mitotane-treated birds did not decrease during the stress response, but the pre-stress immune activity of these birds did not differ from that of vehicle-treated birds. These results suggest that elevated plasma CORT during stress is primarily responsible for mediating stress-induced suppression of innate immune activity. [ABSTRACT FROM AUTHOR]

Stress-induced immunosuppression is one of the most common hazards in poultry intensive production, which often leads to vaccination failure and severe economic losses. At present, there is no report about the function and mechanism of circulating miRNA on stress-induced immunosuppression affecting immune response. In this study, the changes of circulating miR-20a-5p under stress-induced immunosuppressive condition were analyzed by qRT-PCR, and the key time points, tissues and mechanisms for functional regulation of miR-20a-5p in the process of stress-induced immunosuppression affecting avian influenza virus (AIV) vaccine immune response were identified. The results showed that stress-induced immunosuppression down-regulated miR-20a-5p and further affected AIV vaccine immune response, in which 5 day post immunization (dpi) was a key time point, and the heart, lung, and proventriculus were the important tissues. The game relationship analysis between miR-20a-5p and its target nuclear receptor subfamily 4 group A member 3 (NR4A3) gene showed that "miR-20a-5p/NR4A3" pathway was the potential key mechanism of this process, especially for heart and lung. This study provides insights into the molecular mechanisms of stress-induced immunosuppression affecting immune response. • Stress-induced immunosuppression can cause the changes of circulating miR-20a-5p. • "miR-20a-5p/NR4A3" is the key mechanism of immunosuppression affecting immunity. • 5 dpi and heart, lung are the key time-point and tissues, respectively. [ABSTRACT FROM AUTHOR]

Activating the immune system has associated fitness costs, both immediate costs in the form of reduced current reproduction and long-term costs in the form of reduced life span and future reproduction. This indicates that immune system activation can be an important agent in life history trade-offs. In this review, we evaluate the importance of four currencies generally considered as potential mediators of the costs of immune responses in ecological studies: (1) energetic costs, (2) nutrient costs, (3) autoimmunity and (4) oxidative stress, which may be responsible for these trade-offs. A meta-analysis revealed significant elevation of energy consumption during an immune response; however, the magnitude of this energetic cost was only 5–15%. In a direct comparison using similar immune system activation in tits, energetic savings in terms of lowered feeding rate was seven times higher than energetic costs of mounting an immune response. These results do not support the hypothesis that energy is the key proximate currency mediating the costs of immunity. Nutrient savings from immunosuppression seem to be even less beneficial as this constitutes only a minor part of the daily nutrient turnover in the body. In our view, there are some indications that oxidative stress can be an important currency that could mediate both short-term and long-term costs of immune system activation, although direct evidence is so far limited. The importance of autoimmune responses is at this point hard to evaluate owing to limited empirical studies in wild animals. [Copyright &y& Elsevier]

Heavy physical work can result in physiological stress and suppressed immune function. Accordingly, long-distance migrant birds that fly for thousands of km within days can be expected to show immunosuppression, and hence be more vulnerable to infections en route. The red knot Calidris canutus Linnaeus is a long-distance migrant shorebird. We flew red knots the equivalent of 1500 km over 6 days in a wind tunnel. The humoral and cell-mediated immune responses of the flyers were compared to those of non-flying controls. Humoral immunity was measured as antibody production against injected diphtheria and tetanus antigens, and cell-mediated response as phytohemagglutinin-induced wing-web swelling. Blood corticosterone levels, which may modulate immune function, were measured in parallel. The long flights had no detectable effects on humoral or cell-mediated immune responses, or on corticosterone levels. Thus, flight performance per se may not be particularly stressful or immunosuppressive in red knots. Some birds assigned as flyers refused to fly for extended periods. Before flights started, these non-flyers had significantly lower antibody responses against tetanus than the birds that carried out the full flight program. This suggests that only birds in good physical condition may be willing to take on heavy exercise. We conclude that these long-distance migrants appear well adapted to the work load induced by long flights, enabling them to cope with long flight distances without increased stress levels and suppression of immunity. Whether this also applies in the wild, where the migrating birds may face adverse weather and food conditions, remains to be investigated. [ABSTRACT FROM AUTHOR]

According to life-history theory, a condition-dependent trade-off between reproductive performance and immune function might be expected, with only superior individuals being able to allocate many resources into reproduction without having detrimental effects on their immune system. However, little attention has been paid to the possibility that annual variations in environmentally and socially induced stress levels modify this trade-off. We analysed haematological parameters and investigated the relationship between male immunological condition and reproductive performance as measured by reproductive effort and success in a colony of the highly polygynous red bishop ( Euplectes orix) for five consecutive breeding seasons. Haematological parameters can be used to assess an individuals’ stress level, and especially the heterophile/lymphocyte ratio (H/L ratio) is known to increase in response to a wide variety of stressors. Relative basophile counts, heterophile counts, lymphocyte counts, absolute leukocyte counts and H/L ratios of territorial males varied significantly among seasons. Both relative heterophile counts and H/L ratios were significantly positive related to overall breeding activity within the colony as measured in terms of total number of nests accepted and total number of eggs laid in the study colony within a breeding season. The relationship between immunological condition (as assessed by relative lymphocyte and heterophil counts and the H/L ratio) and both male reproductive effort (as measured by the number of nests built by the territorial males) and reproductive success (as measured by the number of nests accepted) varied considerably among seasons, ranging from significant negative to significant positive correlations. Across seasons, we found a significant negative relationship between the within-season correlation coefficients of individual H/L ratios against reproductive performance and the average H/L ratio of all territorial males in that season. Thus, a positive association between the immunological condition of a male and his reproductive performance (indicated by a negative correlation between H/L ratio and reproductive performance) exists only in seasons with high average H/L ratios (i.e. high average stress levels). We conclude that the trade-off between immunological condition and male reproductive performance might be important only in seasons with an overall reduced level of male immunological condition due to environmentally and/or socially induced stress and immunosuppressive conditions. [ABSTRACT FROM AUTHOR]

While host stress in vertebrate populations has often been linked to outbreaks of epidemics, which are attributed to the immuno-compromise of the stressed hosts, no predictions have been made about the response of invertebrate host populations to stressful conditions. Experiments conducted on individual invertebrate hosts, however, suggest that starved hosts may be a poor resource for parasites and that heavily infected old hosts may be more susceptible to stress, causing parasite populations to decline when their host population faces food shortages. In this epidemiological experiment, we exposed infected and uninfected Daphnia magna populations, which had been kept for many generations under a constant high food supply, to reduced food resources. Using the microsporidian gut parasite Glugoides intestinalis, which is exclusively horizontally transmitted, we tracked changes in parasite and host population size as well as host body length to. elucidate how food shortages for the hosts influence host and parasite population dynamics. In both infected and uninfected populations, food shortage led to an approximately equal reduction in host density and changes in host body length distribution. Large hosts suffered a higher mortality than smaller hosts, which significantly reduced the mean body length in the host populations; however, this change was stronger in the infected populations and went hand- in-hand with a reduction in parasite spore load (a measure of intensity of infection) and prevalence. This effect disappeared after six weeks of food shortage, when the populations reached a new equilibrium. Our results indicate that in this system food stress impairs parasite spread and that host mortality is an important factor in regulating parasite abundance at the population level. [ABSTRACT FROM AUTHOR]

Reviewing the literature concerning the possible role of psychosocial factors in the aetiology of inflammatory periodontal diseases, it may he concluded that there is evidence which strongly suggests that emotional stress is one of the predisposing factors to ANUG. On the other hand, it is not clear that the scientific evidence is sufficient lo substantiate the hypothesis that psychosocial factors are of aetiological importance in periodontitis. The proposed mechanisms which may mediate the putative relationship between psychosocial conditions and inflammatory periodontal diseases remain to be tested. However, psychoneuroimmunologic studies make lowered host resistance especially interesting as a possible mechanism. Although available studies do not definitively support causal relationships, they suggest that psychosocial factors may be involved in the aetiology of inflammatory periodontal diseases, which, in turn, would relate to clinical management of these conditions. [ABSTRACT FROM AUTHOR]

The molecular mechanism of stress-induced immunosuppression (SIS) in certain poultry immune organs is not completely clear. In this study, we constructed a stress immunosuppression model by selecting 180 healthy 7-day-old Gushi chickens and dividing them randomly into two groups: a D&#95;T group and a B&#95;T group. The D&#95;T group was given dexamethasone, and the B&#95;T group was given normal saline, according to the treatment method established and reported in our previous study. Thymus samples were subsequently taken from both groups. RNA-seq was used to sequence the transcriptomes of the thymus samples from both groups, and 1278 significant differentially expressed genes (DEGs) were obtained, of which 845 genes were up-regulated and 433 genes were down-regulated (padj<0.05, |FC| ≥ 2, FPKM>1). We identified immune-related gene ontology (GO) terms including immune system processes, immune system process regulation, and T cell activation. The results of KEGG (http: //www.kegg.jp) analysis showed that the DEGs are involved in a variety of immune-related pathways, such as cytokine-cytokine receptor interactions, Jak-STAT signaling pathways, and cell adhesion molecules (CAMs). The cytokine-cytokine receptor interaction pathway involves the DEGs CCR6, CCR5, CD40LG and FAS. The DEGs in the Jak-STAT signaling pathway were SPRY2, BCL2L1. These DEGS play an important role in cell apoptosis. CD40L, CD8, among other genes, are involved in the CAMs pathway. The results of this study add to existing data on the genomic study of stress affecting immune function, and provide a basis for further studies of the molecular mechanisms of stress-influenced immune function., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)