Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease
Introduction
Many lines of evidence, ranging from pathologic analyses to epidemiological studies, show that atherosclerosis is intrinsically an inflammatory disease (Libby, Ridker, & Maseri, 2002; Ross, 1999). The initiation of inflammatory reactions is a complex process involving the coordinated expression of cellular adhesion molecules and chemotactic cytokines (chemokines), which recruit blood-derived leukocytes to the site of inflammation. The recruitment of leukocytes by chemokines into the sub-endothelium of the vascular wall is a major aspect of atherogenesis. T lymphocytes are among the first cells to infiltrate the sub-endothelium (Libby et al., 2002; Ross, 1999; Song, Leung, & Schindler, 2001), and remain a major local cell population throughout the atherosclerotic process. These T cells subsequently secrete cytokines (e.g., interferon-γ, TNF-α, and interleukin-2), which further promote the inflammatory atherosclerotic response. Monocytes are another critical constituent of the atherosclerotic response. Once resident in the vessel wall, monocytes develop into macrophages as they take up oxidized low-density lipoprotein and differentiate into so-called foam cells. Macrophages and lipid-laden foam cells are implicated as prime culprits in the events that ultimately complicate atherosclerosis (Libby et al., 2002; Ross, 1999).
It is likely that the endothelium itself initiates this process of leukocyte recruitment (Libby et al., 2002; Reape & Groot, 1999; Shin, Szuba, & Rockson, 2002). Endothelial cells can secrete numerous chemokines upon activation by molecules derived from the circulation and adjacent cells (e.g., Burke-Gaffney, Brooks, & Bogle, 2002; Kotani, Hori, Matsumura, & Uchiyama, 2002; Mach et al., 1999; Qi & Kreutzer, 1995; Seeger et al., 2002). In fact, virtually all cardiovascular risk factors (e.g., increased LDL levels, hypertension, diabetes, obesity, and infection) are capable of promoting an inflammatory response in endothelial cells with the concomitant secretion of inflammatory mediators (Libby et al., 2002). Chemokines secreted by endothelial cells include Growth Regulated Oncogene (GRO, which has an α,β, and γ sub-type), Epithelial Neutrophil Activating peptide-78 (ENA-78), Neutrophil Activating Protein-2 (NAP-2), and Interleukin 8 (IL-8). These chemokines are all ligands for the pleiotrophic chemokine receptor CXCR2, whereas IL-8 can also stimulate the chemokine receptor CXCR1. Other examples of chemokines secreted by endothelial cells are Interferon-γ Inducible Protein-10 (IP-10), which binds to the chemokine receptor CXCR3, and Regulated on Activation Normal T cell Expressed and Secreted (RANTES), which is a ligand for several chemokine receptors including CCR5 (Burke-Gaffney et al., 2002; Oppenheim, Zachariae, & Goetzl, 2000; Wang, Su, Gong, & Oppenheim, 1998).
Acute psychological stressors are known to modulate this process of leukocyte trafficking and to enhance subsequent cellular immune responses in the local tissues (Dhabhar and McEwen, 1997, Dhabhar and McEwen, 1999; Dhabhar, Miller, Stein, McEwen, & Spencer, 1994; Sanders & Straub, 2002). If, as the exisiting evidence suggests, migratory responses of leukocytes are crucial in the development of atherosclerotic lesions, then acute stress may influence atherosclerotic plaque formation in part through its effects on leukocyte migration and recruitment.
The magnitude of cardiovascular system responses to acute stressors (“cardiovascular reactivity”) is considered a potential risk factor for cardiovascular disease progression and its acute clinical manifestations (Kop, 1999; Krantz, Kop, Santiago, & Gottdiener, 1996; Rozanski, Blumenthal, & Kaplan, 1999; Sheps et al., 2002). Likewise, immune reactivity (the response of immune parameters during acute stress) has been proposed as a potential predictor for vulnerability to immune mediated disease (Cacioppo et al., 1998; Cohen et al., 2002; Sanders & Straub, 2002). Cardiovascular and immune reactivity are correlated phenomena that are both determined by sympathetic nervous system activation (Cacioppo et al., 1995; Sgoutas-Emch et al., 1994; Uchino, Cacioppo, Malarkey, & Glaser, 1995). Thus, it is possible that the observed link between sympathetic cardiac reactivity and cardiovascular disease manifestations is mediated in part through immunological pathways. The present study examined the effects of an acute stressor on the redistribution of T cells (CD3+) and monocytes that express the chemokine receptors CCR5, CCR6, CXCR1, CXCR2, CXCR3, and CXCR4. The findings suggest that immune reactivity, or at least some aspects of this phenomenon, may also be relevant to the development of cardiovascular disease.
Section snippets
Participants
Forty-four university undergraduates (mean age 20, range 18–27 years, 22 male) volunteered to participate in this study as part of a longitudinal study on psychosocial factors and wound healing. Participants gave written informed consent and received a monetary compensation for their participation. Participants were ineligible if they were using medication, or reported health problems indicative of cardiovascular, inflammatory, or infectious disease.
Procedures
In preparation for the study, participants
Psychological and cardiovascular reactions
Analysis of POMS subscales indicated that the speech tasks were perceived as stressful, as evidenced by increases in tension-anxiety (Mbaseline 3.1 (SEM 0.5), Mtask 9.3 (SEM 0.8), F(43)=21.34,p<.001) and anger-hostility (Mbaseline 0.18 (SEM 0.3), Mtask 2.3 (SEM 0.6), F(43)=10.73,p<.01). Replicating prior research, analyses confirmed that the acute psychosocial stressor elevated HR, increased cardiac sympathetic activation, and produced vagal withdrawal (see Table 1). Because gender and body
Discussion
T lymphocytes and monocytes/macrophages are the most abundant cells found in the atherosclerotic plaque (Libby et al., 2002; Ross, 1999). These cells are attracted towards the activated endothelium by chemokines that are initially secreted by the local endothelial cells. The present study investigated the effects of an acute stressor (public speaking) on the mobilization of T cells and monocytes that express receptors for these chemotactic factors. Whereas the total number of circulating CD3+
Acknowledgements
This study would have been impossible without the dedicated efforts of April C. Logue, BS, Janet Schulte, BS, Josja K. Eggen, MA, and Kelly Dillon, BA, Jason Davis, BA, Sunhee Lee, PhD, Jean Tillie, BS, and Alison Saul, BS. The study was performed at The Ohio State General Clinical Research Center (GCRC), with special thanks to Linda Mahoney, RN, and Diane L. Habash, PhD, and funded by the National Institute of Health (P50 DE-13749).
References (49)
- et al.
Catecholamine-induced leukocytosis: early observations, current research, and future directions
Brain Behav. Immun.
(1996) - et al.
Regulation of chemokine expression in atherosclerosis
Vasc. Phamacol.
(2002) - et al.
Ambulatory measurement of respiratory sinus arrhythmia and respiration rate
Biol. Psychol.
(1995) - et al.
Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking
Brain Behav. Immun.
(1997) - et al.
Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations
Brain Behav. Immun.
(1994) - et al.
Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5
Immunol. Lett.
(2002) - et al.
Mental stress as a trigger of myocardial ischemia and infarction
Cardiol. Clin.
(1996) - et al.
Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes
Am. J. Pathol.
(2002) - et al.
Leukocyte adhesion molecule expression and T cell naive/memory status following isoproterenol infusion
J. Neuroimmunol.
(2000) - et al.
Chemokines and atherosclerosis
Atherosclerosis
(1999)
Norepinephrine, the β-adrenergic receptor, and immunity
Brain Behav. Immun.
The role of chemokines in human cardiovascular pathology: enhanced biological insights
Atherosclerosis
Individual differences in cortisol responses to a laboratory speech task and their relationship to responses to stressful daily events
Biol. Psychol.
Cardiovascular and immune responses to acute psychological stress in young and old women: A meta-analysis
Psychosom. Med.
Heart rate variability: Origins, methods, and interpretive caveats
Psychophysiology
Cardiac psychophysiology and autonomic space in humans: Empirical perspectives and conceptual implications
Psychol. Bull.
An approach to artifact identification: Application to heart period data
Psychophysiology
The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry
Nature
Social neuroscience: Autonomic, neuroendocrine, and immune responses to stress
Psychophysiology
Autonomic, neuroendocrine, and immune responses to psychological stress: The reactivity hypothesis
Ann. N. Y. Acad. Sci.
Heterogeneity in neuroendocrine and immune responses to brief psychological stressors as a function of autonomic cardiac activation
Psychosom. Med.
The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells
Nature
CCR7 expression and memory T cell diversity in humans
J. Immunol.
Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire
J. Immunol.
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