Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease

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Abstract

T lymphocytes and monocytes/macrophages are the most abundant cells found in the atherosclerotic plaque. These cells can migrate towards the activated endothelium through the local release of chemotactic cytokines, or chemokines. Given the important role of leukocyte migration in atherosclerosis and the role of stress in mediating leukocyte trafficking, 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. Forty-four undergraduate students underwent a public speaking task. The acute stressor induced sympathetic cardiac activation, parasympathetic cardiac withdrawal, lymphocytosis, and monocytosis (all p<.001). Although the total number of T lymphocytes did not change, there was a selective increase in the number of circulating T cells expressing CXCR2, CXCR3, and CCR5. The ligands of these receptors are chemokines known to be secreted by activated endothelial cells. Analyses of individual differences in stress-induced responses demonstrated a positive relationship between sympathetic cardiac reactivity and mobilization of the various T cell subsets (.35<r<.56;p<.05). For the monocytes, all sub-populations increased in parallel with total monocyte numbers, with no relation to changes in sympathetic cardiac drive. These results indicate that acute stress induces a mobilization of T cells that are primed to respond to inflamed endothelium. Acute stressors may thus promote the recruitment of circulating immune cells into the sub-endothelia, and therefore accelerate atherosclerotic plaque formation and potentially contribute to the complications that follow acute stressful events. This mechanism may help explain the link between stress, reactivity, and 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).

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