Suppressed monocyte gene expression profile in men versus women with PTSD
Research highlights
► Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). ► There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. ► In contrast, preliminary data from our pilot sample of female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. ► The results indicate differential patterns of monocyte gene expression in PTSD, and are suggestive of gender dimorphism in biologic pathways activated in PTSD.
Introduction
Posttraumatic Stress Disorder (PTSD) is highly prevalent in both military and civilian populations, is chronic and often accompanied by substance abuse, depression, difficulties with interpersonal relationships, poorer occupational functioning and increased physical health problems (Kulka et al., 1990). A number of studies have demonstrated that PTSD is associated with alterations in immune function (Hoge et al., 2009). Specifically, PTSD is associated with enhanced cellular immune responses (Altemus et al., 2003, Laudenslager et al., 1998, Watson et al., 1993), activated T lymphocytes (Wilson et al., 1999) and impaired humoral immunity, as indexed by higher antibody responses to cytomegalovirus levels (Uddin et al., 2010). PTSD has also been shown to be associated with increased levels of some inflammatory cytokines (Maes et al., 1999a, Spivak et al., 1997, Sutherland et al., 2003). Finally, PTSD is associated with increased levels of C-reactive protein (Miller et al., 2001), an index of systemic inflammatory activity, though this has not been found in all studies (Sondergaard et al., 2004). These findings of altered immune functioning in PTSD have important implications for understanding the high rates of cardiovascular (Cohen et al., 2009, Kubzansky et al., 2007), musculoskeletal, and neurocognitive disorders associated with PTSD (reviewed in Schnurr et al. (2000)). Chronic inflammation is well known to be associated with a broad spectrum of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and possibly neuropsychiatric disorders.
Gene expression microarray analysis has facilitated the discovery of genes/pathways/proteins associated with biological and pathological processes. Only in the past few years has this powerful tool been used to elucidate mechanisms of action for psychiatric disorders. Microarray studies in peripheral immune cells in PTSD have the potential to test hypotheses about immune function as well as to explore biological pathways that are expressed in both the brain and periphery (e.g., glucocorticoid signaling). For example, recent investigations using microarrays and peripheral blood mononuclear cells (PBMC) or lymphocytes have shown that major psychiatric disorders including depression, anxiety, schizophrenia and Alzheimer’s disease as well as chronic stress perturb multiple biological pathways measurable in peripheral immune cells (Irwin, 1999, Maes et al., 1998, Maes et al., 1999b, Ohmori et al., 2005, Schwarz et al., 2001a, Schwarz et al., 2001b).
The first study of gene expression in peripheral blood mononuclear cells (PBMCs) in PTSD came from a study conducted in Israel (Segman et al., 2005). This study examined gene expression patterns from 24 trauma victims, men and women, who were treated in the hospital emergency department in Jerusalem within hours of a traumatic event and 4 months later. Only 13 met the clinical criteria for PTSD; however, the signature profile did correlate with the severity of the PTSD symptom clusters and several differentially expressed genes were described as having a role in stress. A second study recently published by Yehuda et al. (2009) examined gene expression from whole blood in 35 subjects exposed to the World Trade Center attack. The 15 subjects with PTSD showed significant differences from the controls in a number of genes related to immune function, HPA activity, and signal transduction. In particular, this study found decreased expression of the glucocorticoid receptor chaperone protein gene, FKBP5, which extended a previous study showing that specific polymorphisms of the FKBP5 gene interact with severity of child abuse to predict risk for adult PTSD (Binder et al., 2008). It is very likely that differences in findings from different studies may in part be related to the heterogeneity of different cell types used for microarrays. One important study suggests that cell composition, in addition to age and gender, can cause variation in microarray data (Whitney et al., 2003). For example, lymphocytes are a diverse group of cells in the periphery that produce a number of hormones such as ACTH, endorphins, insulin-like growth factor and somatostatin as well as cytokines. In a study of acute stress using lymphocytes in a microarray panel in 10 graduate students before and after an entrance examination, 70 genes were significantly responsive, in spite of individually different baseline activity (Rokutan et al., 2005).
We examined gene expression profiles in monocytes in healthy men and women with and without chronic PTSD. Monocytes are peripheral immune cells that can respond to foreign antigens as well as modulate the immune system by producing inflammatory cytokines that can additionally induce sickness behavior (Dantzer et al., 2008, Middle et al., 2000, Watkins and Maier, 2005). We chose to use CD14+ monocytes for gene expression profiling in PTSD for several reasons. The primary reason is that we wished to limit sources of heterogeneity by restricting our analyses to a homogeneous cell type. Secondly, CD14+ monocytes are relatively less differentiated than most immune cells and have a high degree of plasticity (Kuwana et al., 2003). Furthermore, monocytes (Gidron et al., 2003, Maes et al., 1999b) have demonstrated reactivity, in vivo, to psychological challenges. Our overall hypothesis was that subjects with chronic PTSD will show evidence of chronic inflammation. Given that gender is a well-established risk factor for autoimmune disorders (Fairweather et al., 2008) and that women may have greater inflammatory responses to endotoxin and psychological stress compared with men (Rohleder et al., 2001, van Eijk et al., 2007), we examined a pilot sample of healthy women with and without PTSD to examine gender differences in immune activation. Our second hypothesis was that gene expression for FKBP5 would be decreased in PTSD subjects similar to previously published results (Binder et al., 2008, Yehuda et al., 2009). Finally, given the lack of an established biological marker for PTSD, we tested the hypothesis that PTSD would be associated with an altered gene expression profile that would be expressed and detectable in peripheral monocytes.
Section snippets
Subjects
cDNA microarray gene expressions were analyzed in monocytes collected from a sample of 49 men (PTSD+ N = 24, PTSD− control N = 25) and 18 women (PTSD+ N = 10, PTSD− control N = 8). Medically healthy male and female subjects were recruited from the community by internet and newspaper advertisements and from the San Francisco Veterans Affairs Medical Center (SFVAMC) PTSD Outpatient Program by fliers and brochures. As such, the study subjects should be considered a convenience sample. All subjects were
Male sample
Demographic and clinical details are presented in Table 1. Male PTSD+ participants were not significantly different from male PTSD− controls in age, marital status, or trauma exposure. Approximate duration of time since exposure to the traumatic event ranged from 6 months to 28 years. However, male PTSD+ participants had significantly less education and were significantly more likely to have current MDD or a lifetime history of MDD. No participants fulfilled criteria for alcohol abuse or
Discussion
The primary finding of this research was that monocytes in healthy male PTSD subjects showed a predominant pattern of decreased gene expression. These results are consistent with the finding of diminished gene expression of transcription factors reported by Segman et al. (2005). Notable categories of decreased expression pertain to cytokine/chemokine signaling, platelet function, and histone activity. Thus, there was no evidence for chronic inflammation in our male PTSD subjects. In contrast,
Conflict of interest statement
All authors declare that there are no conflicts of interest.
Acknowledgments
We thank Cyrus Calosing and Thomas Metzler for excellent technical assistance. This research was supported in part by grants from the Department of Defense (W81XWH-05-2-0094), the Mental Illness Research and Education Clinical Center (MIRECC) of the US Veterans Health Administration, and the National Institute for Mental Health (T.C.N.: R01 MH73978). This material is the result of work supported with resources and the use of facilities at the Veterans Administration Medical Center, San
References (50)
- et al.
Mood disorders in the medically ill: scientific review and recommendations
Biol. Psychiatry
(2005) - et al.
Sex differences in autoimmune disease from a pathological perspective
Am. J. Pathol.
(2008) - et al.
Psychological factors correlate meaningfully with percent-monocytes among acute coronary syndrome patients
Brain Behav. Immun.
(2003) - et al.
17-Beta-estradiol regulates expression of genes that function in macrophage activation and cholesterol homeostasis
J. Steroid Biochem. Mol. Biol.
(2002) - et al.
Elevated cytotoxicity in combat veterans with long-term post-traumatic stress disorder: preliminary observations
Brain Behav. Immun.
(1998) - et al.
Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events
Biol. Psychiatry
(1999) - et al.
The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety
Cytokine
(1998) - et al.
A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling
Biol. Psychiatry
(2008) - et al.
C-reactive protein and interleukin 6 receptor in post-traumatic stress disorder: a pilot study
Cytokine
(2001) - et al.
Gender differences in stimulated cytokine production following acute psychological stress
Brain Behav. Immun.
(2009)
Invasive chronic inflammatory monocyte phenotype in subjects with high HIV-1 viral load
J. Neuroimmunol.
T-helper-1 and T-helper-2 responses in psychiatric disorders
Brain Behav. Immun.
The Th2-hypothesis of schizophrenia: a strategy to identify a subgroup of schizophrenia caused by immune mechanisms
Med. Hypotheses
The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder
Clin. Chim. Acta
Elevated levels of serum interleukin-1 beta in combat-related posttraumatic stress disorder
Biol. Psychiatry
Disturbance of pro-inflammatory cytokines in post-traumatic psychopathology
Cytokine
Phenotype of blood lymphocytes in PTSD suggests chronic immune activation
Psychosomatics
Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks
Biol. Psychiatry
Enhanced cellular immune response in women with PTSD related to childhood abuse
Am. J. Psychiatry
Controlling the false discovery rate – a practical and powerful approach to multiple testing
J. R. Statist. Soc. Ser. B Methodol.
Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults
J. Am. Med. Assoc.
The development of a clinician-administered PTSD scale
J. Trauma. Stress
Cytokines, acute-phase proteins, and hormones: IL-1 and TNF-alpha production in contact-mediated activation of monocytes by T lymphocytes
Ann. NY Acad. Sci.
Posttraumatic stress disorder and health-related quality of life in patients with coronary heart disease: findings from the heart and soul study
Arch. Gen. Psychiatry
Psychological stress and disease
JAMA
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2021, Neurobiology of StressCitation Excerpt :Finally, expression of genes located in the HLA region (Fig. 3) have also shown to be associated with PTSD (Sarapas et al., 2011; Yehuda et al., 2009; Mehta et al., 2013). Consistent with these studies, gene-set enrichment analyses further implicate inflammatory and immune pathways in PTSD, including pathways involved in the immune response (Mehta et al., 2013; Neylan et al., 2011; Breen et al., 2015, 2018), cytokine-cytokine interactions (Mehta et al., 2018; Neylan et al., 2011), and the complement system (Bam et al., 2016a). The PTSD-associated inflammatory gene expression changes reported are consistent with alterations in epigenetic profiles, as alterations in DNA methylation are capable of regulating gene expression and are observed in PTSD (Morrison et al., 2019).