Psychosocial Distress Mediates Immune Dysregulation Through Alterations in Global Epigenetic Patterns and Chromatin Remodeling Proteins

Psychosocial distress, characterized by increased perceived stress, anxiety and mood disturbance, is a common response of women to a diagnosis of breast cancer (Northouse, 1992; Pettingale et al., 1988; Stark and House, 2000; Witek-Janusek et al., 2007). This psychosocial distress leads to activation of the hypothalamic-pituitary-adrenocortical (HPA) axis and increased circulating glucocorticoids (GCs) (Chrousos, 2000; Chrousos and Gold, 1992; Schoneveld and Cidlowski, 2007). Increased psychosocial distress and increased HPA activation can lead to immune dysregulation consisting of reduced natural killer (NK) cell activity (NKCA) (Biondi, 2001; Kiecolt-Glaser et al., 1987; Kiecolt-Glaser et al., 2002; Witek-Janusek et al., 2008; Witek-Janusek et al., 2007). This is of particular relevance to women with breast cancer as altered immune cell function is important for tumor control (Curcio et al., 2003; D\u27Anello et al., 2010; Diefenbach and Raulet, 2002; Hartman et al., 2011; Kishimoto, 2005; Knupfer and Preiss, 2007; Street et al., 2001; van den Broek et al., 1996). The psychological distress in response to a diagnosis of breast cancer diagnosis has relevance for women with breast cancer, as it may contribute to poor cancer outcome. Yet little is known about the molecular mechanism(s) by which psychosocial distress results in NK cell dysregulation. The overall purpose of this project was to evaluate a potential mechanism posited to underlie altered NK cell function observed in women with breast cancer. Increased psychosocial distress increases GCs like cortisol which can impact NK cell function; therefore cortisol levels were measured. Morning cortisol rise inversely correlated with NKCA, such that women with decreased NKCA exhibited an elevation in the morning cortisol rise. Additionally, in vitro treatment of a human NK cell line, NK92 cells, treated with a synthetic GC (dexamethasone) resulted in decreased NKCA. Together these results suggest that cortisol altered lytic function of NK cells. As GCs have been shown to alter cell function by altering epigenetic patterns, global histone modifications were investigated. In both ex vivo analysis of NK cells derived from peripheral blood of women with breast cancer and NK92 cells treated with GCs significant reductions in global acetylation of histone 4 lysine 8 (H4-K8-Ac) were observed, when compared to the age-matched Control women or untreated NK92 cells, respectively. These reductions in H4-K8-Ac correlated with NK cell lytic function as measured by NKCA and intracellular perforin levels in NK cells. Further others show GCs alter epigenetic patterns through recruitment of HDACs, thus this was investigated. Findings show decreased global H4-K8-Ac patterns in NK cells were associated with increased nuclear localization of HDAC2, suggesting that GCs recruit HDAC2 into the nucleus causing decreased global H4-K8-Ac and NKCA. These data identify decreased global H4-K8-Ac and increased nuclear localization of HDAC2 as potential markers of decreased NK cell lytic activity in women experiencing psychosocial distress. This mechanistic insight advances the field of psychoneuroimmunology by identifying both an epigenetic modification (H4-K8-Ac) and a chromatin remodeling protein (HDAC2) as indicators of GC mediated immune dysregulation in NK cells of women experiencing psychosocial distress

Persistent Infiltration and Impaired Response of Peripherally-Derived Monocytes after Traumatic Brain Injury in the Aged Brain.

Traumatic brain injury (TBI) is a leading cause for neurological disabilities world-wide. TBI occurs most frequently among the elderly population, and elderly TBI survivors suffer from reduced recovery and poorer quality of life. The effect of age on the pathophysiology of TBI is still poorly understood. We previously established that peripherally-derived monocytes (CCR2⁺) infiltrate the injured brain and contribute to chronic TBI-induced cognitive deficits in young animals. Furthermore, age was shown to amplify monocyte infiltration acutely after injury. In the current study, we investigated the impact of age on the subchronic response of peripherally-derived monocytes (CD45hi; CCR2⁺) and their role in the development of chronic cognitive deficits. In the aged brain, there was a significant increase in the number of peripherally-derived monocytes after injury compared to young, injured animals. The infiltration rate of peripherally-derived monocytes remained elevated subchronically and corresponded with enhanced expression of CCR2 chemotactic ligands. Interestingly, the myeloid cell populations observed in injured aged brains had impaired anti-inflammatory responses compared to those in young animals. Additionally, in the aged animals, there was an expansion of the blood CCR2⁺ monocyte population after injury that was not present in the young animals. Importantly, knocking out CCR2 to inhibit infiltration of peripherally-derived monocytes prevented chronic TBI-induced spatial memory deficits in the aged mice. Altogether, these results demonstrate the critical effects of age on the peripherally-derived monocyte response during the progression of TBI pathophysiology

In vivo metabolic imaging of Traumatic Brain Injury.

Complex alterations in cerebral energetic metabolism arise after traumatic brain injury (TBI). To date, methods allowing for metabolic evaluation are highly invasive, limiting our understanding of metabolic impairments associated with TBI pathogenesis. We investigated whether 13C MRSI of hyperpolarized (HP) [1-13C] pyruvate, a non-invasive metabolic imaging method, could detect metabolic changes in controlled cortical injury (CCI) mice (n = 57). Our results show that HP [1-13C] lactate-to-pyruvate ratios were increased in the injured cortex at acute (12/24 hours) and sub-acute (7 days) time points after injury, in line with decreased pyruvate dehydrogenase (PDH) activity, suggesting impairment of the oxidative phosphorylation pathway. We then used the colony-stimulating factor-1 receptor inhibitor PLX5622 to deplete brain resident microglia prior to and after CCI, in order to confirm that modulations of HP [1-13C] lactate-to-pyruvate ratios were linked to microglial activation. Despite CCI, the HP [1-13C] lactate-to-pyruvate ratio at the injury cortex of microglia-depleted animals at 7 days post-injury remained unchanged compared to contralateral hemisphere, and PDH activity was not affected. Altogether, our results demonstrate that HP [1-13C] pyruvate has great potential for in vivo non-invasive detection of cerebral metabolism post-TBI, providing a new tool to monitor the effect of therapies targeting microglia/macrophages activation after TBI

Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits.

Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure

Author Correction: Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits.

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