Altered Human Neutrophil Function in Response to Acute Psychological Stress

Objective: To examine the effects of an acute laboratory psychological stress task on neutrophil function, specifically phagocytosis of Escherichia coli and stimulated superoxide production in human neutrophils. There is mounting evidence that acute stress is associated with short-term increases in a number of immune indices. \ud \ud Methods: Participants were 40 (n = 20 females) university students (mean age, 25.9 ± 4.56 years). Blood samples to determine neutrophil function by flow cytometry were taken at the end of resting baseline, during an acute stress task, and during recovery. The stress task was a 10-minute time-pressured mental arithmetic challenge with social evaluation. \ud \ud Results: There was an acute increase in phagocytic ability, $\rho$ = .047, η2p = 0.076, and a reduction of superoxide production, p = .026, η2p = 0.101, associated with the stress task relative to baseline. \ud \ud Conclusion: These findings suggest that neutrophil bactericidal function may be sensitive to mental challenge tasks that provoke acute psychological stress. Further research is needed to replicate the observed psychological stress-induced changes in neutrophil function. \ud \u

Assessing the feasibility and impact of an adapted resistance training intervention, aimed at improving the multi-dimensional health and functional capacity of frail older adults in residential care settings: protocol for a feasibility study

Background Frailty is a common and clinically significant condition in older adults, predominantly due to its association with adverse health outcomes such as hospitalisation, disability and mortality. Exercise interventions have been shown to be a beneficial treatment for frail older adults. However, more high-quality studies are needed within this area to assess the feasibility and impact of these interventions in frail geriatric populations within different settings, and with regards to their impact on broader aspects of health and wellbeing. Methods This study will utilise an interventional, randomised, controlled research design in order to assess the feasibility (acceptability, demand, implementation, practicality, adaptation, integration, expansion) and potential impact (limited-efficacy testing) of a specially adapted resistance training intervention; aimed at improving the multi-dimensional health and functional capacity of frail geriatric care home residents. Discussion The most immediate implication of this research from a scientific perspective is informing the feasibility, and potential efficacy, of a proposed future clinical trial within this setting. Additionally, if the study proves feasible, and the limited-efficacy testing proves positive, this study also has the potential to lead to advancement in the care for frail geriatric populations within residential care settings; and the ability to measurably improve various aspects of health and functional capacity within this population. This study has been granted a favourable ethical opinion by the London Harrow NHS Research Ethics Committee and is sponsored by the University of Birmingham. The findings of this study will be disseminated through publication in open access scientific journals, public engagement events, online via social media, conference presentations and directly to study participants

The immune suppressive properties of damage associated molecular patterns in the setting of sterile traumatic injury

Associated with the development of hospital-acquired infections, major traumatic injury results in an immediate and persistent state of systemic immunosuppression, yet the underlying mechanisms are poorly understood. Detected in the circulation in the minutes, days and weeks following injury, damage associated molecular patterns (DAMPs) are a heterogeneous collection of proteins, lipids and DNA renowned for initiating the systemic inflammatory response syndrome. Suggesting additional immunomodulatory roles in the post-trauma immune response, data are emerging implicating DAMPs as potential mediators of post-trauma immune suppression. Discussing the results of in vitro, in vivo and ex vivo studies, the purpose of this review is to summarise the emerging immune tolerising properties of cytosolic, nuclear and mitochondrial-derived DAMPs. Direct inhibition of neutrophil antimicrobial activities, the induction of endotoxin tolerance in monocytes and macrophages, and the recruitment, activation and expansion of myeloid derived suppressor cells and regulatory T cells are examples of some of the immune suppressive properties assigned to DAMPs so far. Crucially, with studies identifying the molecular mechanisms by which DAMPs promote immune suppression, therapeutic strategies that prevent and/or reverse DAMP-induced immunosuppression have been proposed. Approaches currently under consideration include the use of synthetic polymers, or the delivery of plasma proteins, to scavenge circulating DAMPs, or to treat critically-injured patients with antagonists of DAMP receptors. However, as DAMPs share signalling pathways with pathogen associated molecular patterns, and pro-inflammatory responses are essential for tissue regeneration, these approaches need to be carefully considered in order to ensure that modulating DAMP levels and/or their interaction with immune cells does not negatively impact upon anti-microbial defence and the physiological responses of tissue repair and wound healing

Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation

Major traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly understood. Here, we analyzed pre-hospital blood samples acquired from 62 adult trauma patients (mean age 44 years, range 19–95 years) within 1 h of injury (mean time to sample 39 min, range 13–59 min). We found an immediate impairment in neutrophil extracellular trap (NET) generation in response to phorbol 12-myristate 13-acetate (PMA) stimulation, which persisted into the acute post-injury phase (4–72 h). Reduced NET generation was accompanied by reduced reactive oxygen species production, impaired activation of mitogen-activated protein kinases, and a reduction in neutrophil glucose uptake and metabolism to lactate. Pre-treating neutrophils from healthy subjects with mitochondrial-derived damage-associated molecular patterns (mtDAMPs), whose circulating levels were significantly increased in our trauma patients, reduced NET generation. This mtDAMP-induced impairment in NET formation was associated with an N-formyl peptide mediated activation of AMP-activated protein kinase (AMPK), a negative regulator of aerobic glycolysis and NET formation. Indeed, activation of AMPK via treatment with the AMP-mimetic AICAR significantly reduced neutrophil lactate production in response to PMA stimulation, a phenomenon that we also observed for neutrophils pre-treated with mtDAMPs. Furthermore, the impairment in NET generation induced by mtDAMPs was partially ameliorated by pre-treating neutrophils with the AMPK inhibitor compound C. Taken together, our data demonstrate an immediate trauma-induced impairment in neutrophil anti-microbial function and identify mtDAMP release as a potential initiator of acute post-injury neutrophil dysfunction

Development of depressive symptoms post hip fracture is associated with altered immunosuppressive phenotype in regulatory T and B lymphocytes

Hip fracture is a common physical trauma in older adults that is also associated with a high incidence of new onset depression. The immune system declines with age and is also compromised by physical and psychological stress. This study examined whether hip fracture and depressive symptoms had additive effects upon the aged immune system that might contribute to poor health outcomes after hip fracture. We assessed the frequency of regulatory T cells, Tregs (CD4+ CD25+ Foxp3+) and IL10 production by CD4 T cells, and the frequency and IL10 production by regulatory B cells, Bregs (CD19+ CD24hi CD38hi) in 101 hip fracture patients (81 female) 6 weeks after injury and 43 healthy age-matched controls (28 female). 38 hip fracture patients (37 %) developed depressive symptoms. Hip fracture did not have an effect on circulating Tregs frequency but a significant reduction in the frequency of Bregs was observed in patients who developed depression compared with non-depressed patients (p = 0.001) or healthy controls (p < 0.001). Bregs also showed a significant decline in IL10 production in depressed hip fracture patients compared with controls (p = 0.04) and non-depressed patients (p = 0.01). In contrast, there was an increase in IL10 production by CD4 T cells in hip fracture patients with new onset depression compared to hip fracture patients without depression (p = .04) and healthy controls (p = .02). We conclude that the reduced immunity associated with new onset depression post hip fracture could include a contribution by heightened Tregs function

Bereavement reduces neutrophil oxidative burst only in older adults: role of the HPA axis and immunesenescence

Background The effect of the chronic stress of bereavement on immunity is poorly understood. Previous studies have demonstrated negative effects on immunity in older adults, and those who report higher depressive symptoms. The aim of the present study was to compare the effect of bereavement on neutrophil function in healthy young and old adults, also assessing serum levels of the stress hormones, cortisol and dehydroepiandrosterone sulphate (DHEAS). 41 young (mean age 32 years) and 52 older adults (mean age 72 years), bereaved and non-bereaved, took part in the study. They completed questionnaires on socio-demographic and health behaviour characteristics, as well as psychosocial variables, and provided a blood sample for analysis of neutrophil function (phagocytosis and reactive oxygen species (ROS) production) and stress hormone analysis. Results Bereaved participants in both age groups reported more symptoms of depression and anxiety than controls and scored moderately highly on bereavement-specific questionnaires for these symptoms. Despite this, young bereaved participants showed robust neutrophil function when compared to age-matched non-bereaved controls, and comparable stress hormone levels, while reduced neutrophil ROS production and raised stress hormone levels (cortisol:DHEAS ratio) were seen in the older bereaved group compared to their age-matched controls. Conclusions Reduced neutrophil function among older bereaved participants may be the result of the inability to maintain stress hormone balance, specifically the cortisol:DHEAS ratio

NK cell immunesenescence is increased by psychological but not physical stress in older adults associated with raised cortisol and reduced perforin expression

NK cell cytotoxicity (NKCC) reduces with age and this has been associated previously with increased mortality. The immune response is also modulated by stress, and here, we assessed the effect of the physical stress of hip fracture and the psychological stress of depression on NKCC in an aged immune system. NKCC was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and in 50 healthy age-matched controls (28 female). Thirty-eight patients were depressed at 6 weeks post-injury, and NKCC was reduced in patients who developed depression compared with non-depressed hip fracture patients (p = 0.004) or controls (p

Depressive symptoms post hip fracture in older adults are associated with phenotypic and functional alterations in T cells

Background Ageing is accompanied by reduced immunity, termed immunesenescence. The immune system does not act in isolation and is sensitive to both psychological and physical stress. Hip fracture is a common physical stressor in older adults with a high incidence of new onset depression, which relates to poorer prognosis. We therefore set out to examine the possible synergistic effects of physical stress (hip fracture) and psychological stress (depressive symptoms) on the aged immune system. Results T cell phenotype and function was assessed in 101 hip fracture patients (81 female) 6 weeks after hip fracture and 43 healthy age-matched controls (26 female). 38 fracture patients had depressive symptoms at 6 weeks. T cell frequency (p = .01) and numbers (p = .003) were both lower in depressed hip fracture patients compared to healthy controls. The frequency of senescent CD28-ve (p = .001), CD57+ve (p = .001), KLRG1+ve (p = .03) CD8 T cells, as well as senescent CD28-ve CD4+ve (p = .01) and CD57+ve CD4+ve (p = .003) T cells were higher in depressed hip fracture patients compared with healthy controls and the frequency of CD28-ve CD8 T cells was also higher when compared to patients with hip fracture alone (p = .01). Additionally, activated CD69+ve (p = .005) and HLADR+ve (p

New-Onset Depression Following Hip Fracture Is Associated With Increased Length of Stay in Hospital and Rehabilitation Centers

This article examines the coincident effects of new-onset depression post hip fracture on length of hospital stay, readmission rates, and incidence of infections in older adults. Participants were 101 hip fracture patients aged 60+ years; 38 developed depressive symptoms following their fracture. Infection rates, readmissions to hospital and rehabilitation units, and length of hospital stay were assessed over the 6 months post hip fracture from hospital and general practitioner notes. Patients who developed depression by Week 6 post fracture were likely to spend more time in hospital/rehabilitation wards (p = .02) and more likely to be discharged to a rehabilitation unit (p < .05). There were no group differences in readmissions or infection rates. New-onset depression coincident with hip fracture in older adults is associated with longer hospital ward stays and greater need for rehabilitation