Stress-induced redistribution of immune cells—From barracks to boulevards to battlefields: A tale of three hormones – Curt Richter Award Winner
Introduction
Regulated redistribution of immune cells among different body compartments is essential for effective immune surveillance and salubrious immune function (Butcher, 1990, Sprent and Tough, 1994). The blood is a critical compartment through which immune cells must pass in order to maintain their normal surveillance pathways and to rapidly reach sites of de novo immune activation (e.g., wounding, sterile tissue damage and inflammation, or antigen or pathogen entry) (Springer, 1994). Therefore, the numbers and proportions of leukocytes in the blood provide an important representation of the state of distribution of leukocytes in the body and of the state of activation of the immune system. Numerous studies have shown that stress can significantly affect immune cell distribution and function (for review see: Butts and Sternberg, 2008, Chrousos, 2010, Dhabhar, 2009b, Dhabhar and McEwen, 1997, Glaser and Kiecolt-Glaser, 2005). Stress has been defined as a constellation of events, consisting of a stimulus (stressor), that precipitates a reaction in the brain (stress perception), that in turn activates physiological fight-or-flight systems in the body (biological stress response) (Dhabhar and McEwen, 1997). It is important to recognize that the only mechanism through which a stressor can affect the brain or body is by inducing biological changes in the organism, which highlights the critical importance of stress hormones and physiological stress response. While stress can be harmful when it is chronic or long lasting (Chrousos and Kino, 2007, Glaser and Kiecolt-Glaser, 2005, Irwin et al., 1990, McEwen, 1998), it is often overlooked that a stress response has salubrious adaptive effects in the short run (Dhabhar and McEwen, 2007, Dhabhar and Viswanathan, 2005, Rosenberger et al., 2009). Therefore, a major distinguishing characteristic of stress is duration: Acute or short-term stress has been defined as stress that lasts for a period of minutes to hours, and chronic stress as stress that persists for several hours per day for weeks or months (Dhabhar and McEwen, 1997).
It is well known that acute or short-term stress induces a large-scale redistribution of immune cells in the body (for review see: Dhabhar, 1998, Dhabhar, 2009a, Dhabhar, 2009b). This redistribution is similar across many species, including humans, which suggests that it is evolutionarily significant and likely to confer an adaptive advantage (Dhabhar, 1998, Dhabhar, 2009a, Dhabhar, 2009b). Given the rapid time course and large magnitude of stress-induced immune cell redistribution, these effects of stress are important to take into account while measuring immune function, therapeutically administering stress hormones, and collecting, analyzing, and interpreting experimental and clinical data. Surprisingly, in spite of its importance, immune cell redistribution has been a relatively underappreciated, and clinically untapped, effect of stress.
Although the functional and clinical ramifications of stress-induced leukocyte redistribution have yet to be fully appreciated and harnessed, numerous studies have elegantly examined the effects of stress (Bosch et al., 2003, Brosschot et al., 1994, Dhabhar et al., 1995b, Mills et al., 1995, Schedlowski et al., 1993b, Stefanski and Gr¸ner, 2006), and exercise (Goebel and Mills, 2000, Hong et al., 2004, Nagatomi et al., 2000, Okutsu et al., 2008, Pedersen and Hoffman-Goetz, 2000) on selected leukocyte subpopulations. In a seeming contradiction, human studies have generally shown that acute stress increases blood immune cell numbers relative to resting state, while mouse and rat studies have shown that acute stress decreases blood immune cell numbers. However, these apparent contradictions may mainly be a matter of kinetics and arise when different studies examine different phases of the effects of acute stress on blood immune cell numbers. Therefore, the first series of results presented here comprehensively quantifies the effects of the early and late phases of stress on all major immune cell subpopulations. We test the hypothesis that the increase in blood immune cell numbers (which represents leukocyte mobilization into the blood) occurs early during short-term stress, while the decrease in blood immune cell numbers (which represents leukocyte traffic out of the blood and into tissues) occurs late during acute stress.
Numerous studies have also examined the effects of specific stress hormones on blood immune cell numbers (Benschop et al., 1996, Dale et al., 1974, Dhabhar et al., 1996, Fauci and Dale, 1974, Schedlowski et al., 1993a). Furthermore, it has been shown that adrenalectomy significantly reduces the magnitude of stress-induced decreases in blood leukocytes (Dhabhar et al., 1995b). Taken together, these studies suggest that the principal stress hormones, norepinephrine (NE), epinephrine (EPI) and corticosterone (CORT), that exert the widespread physiological effects of an acute stress response (Dhabhar and McEwen, 2001, Sapolsky et al., 2000), are also the major endocrine mediators of specific phases and redistribution profiles of psychological and physical (exercise) stressors on specific leukocyte subpopulations (Dhabhar and McEwen, 2001). EPI and NE have also been extensively studied as mediators of exercise-induced changes in immune cell distribution (Pedersen and Hoffman-Goetz, 2000). To our knowledge, however, no study has systematically and comprehensively elucidated the effects of stress hormones administered singly and in combination. Such elucidation of the combinatorial effects of stress hormones is important for understanding the differential contributions of NE, EPI, and CORT, that may come into effect as a result of different concentrations and combinations of these hormones being stimulated under different stress conditions (Kvetnansky et al., 1998, Pacak et al., 1998). Therefore, in the second series of results presented here we characterize and quantify individual and combined actions of NE, EPI and CORT, in mediating changes in all major leukocyte subpopulations. We hypothesized that specific stress hormones and their combinations would mediate distinct aspects of stress-induced leukocyte redistribution.
In both series of experiments we quantify changes in leukocyte expression of the adhesion molecule, L-selectin (CD62L) that mediates leukocyte rolling, the first step in the cascade of reactions that leads to leukocyte adhesion and transmigration, critical steps for leukocyte surveillance pathways and leukocyte response to immune activation/inflammation (Butcher and Picker, 1996, Khan et al., 2003, Wedepohl et al., 2011). Given its critical role in the adhesion cascade, we hypothesized that stress and stress hormones would change leukocyte CD62L expression. Additionally, the presence or absence of CD62L on an immune cell can be used to approximate its functional or maturation status. For example, CD62L+ Th and CTLs cells are thought to be either naïve or central memory T cells while CD62L− Th and CTLs are thought to be effector T cells (Seder and Ahmed, 2003). Similarly, CD62L+ monocytes are thought to be classical/inflammatory monocytes while CD62L− monocytes are thought to be non-classical monocytes (Gordon and Taylor, 2005, Tacke and Randolph, 2006). Therefore, we used the presence or absence of CD62L to characterize and quantify the differential effects of stress and stress hormones on specific functional/maturation phenotypes within each leukocyte subpopulation.
Studies such as these are important because they could conceivably lead to clinical applications that harness stress physiology to direct/enhance protective immune responses during vaccination, wound healing, infection, or cancer, to reduce leukocyte traffic to sites of inflammatory/autoimmune reactions, to sequester immune cells in certain compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy, and to monitor as a measure of stress hormone resistance/sensitivity. These studies also have important implications for experimental design and for the interpretation of experimental and clinical/diagnostic data. To our knowledge, these studies are the first to simultaneously quantify stress-induced changes in all major leukocyte subpopulations and their distinct functional subtypes, during the early (mobilization) as well as late (trafficking) phases of the leukocyte redistribution stress response. To our knowledge, these studies are also the first to quantify the combinatorial effects of simultaneously administering stress hormone combinations that mimic and elucidate the effects of NE, EPI, and CORT, which are the major mediators of the stress-induced changes in immune cell distribution. Based on data presented here as well as what is known in the literature, we propose a model explaining how stress hormones represent a “call to arms” and induce the body's “soldiers” (immune cells) to leave their “barracks” (marginated pool, spleen, bone marrow), travel through the “boulevards” (blood vessels) and take up positions at ongoing or potential “battlefields” (e.g., skin, gastro-intestinal tract, uro-genital tract) during or following stress.
Section snippets
Animals
Male Sprague Dawley rats (200–300 g) (Harlan Sprague Dawley, Indianapolis, IN) were used in all experiments. Animals were housed (3 per cage) in the accredited (American Association of Accreditation of Laboratory Animal Care) animal facilities of The Rockefeller University (New York, NY). Experiments were conducted according to protocols approved by The Rockefeller University Laboratory Animal Care and Use Committee. Animal rooms were maintained on a 12-h light-dark cycle (lights on at 7 a.m.
Acute stress-induced changes in norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT)
Fig. 1 shows stress-induced changes in NE, EPI, and CORT. Acute stress increased circulating concentrations of the three principal stress hormones, NE (resting = 3881 + 550 pg/ml; stress = 5245 + 659 pg/ml, nss), EPI (resting = 7537 + 910 pg/ml; stress = 9846 + 540 pg/ml, nss), and CORT (resting = 65 + 31 ng/ml; stress = 791 + 44 ng/ml, p < 0.05). Relative to resting state baseline levels, NE and EPI reached peak concentrations at 6 min after the beginning of stress (nss), while circulating CORT showed a significant increase
Kinetics of stress-induced mobilization and trafficking of blood immune cells
It is important to recognize that a short-term increase in blood leukocytes (as seen during acute stress) reflects a mobilization of cells into the blood from certain compartments (e.g., marginated pool, spleen, bone marrow, lung, lymph nodes). In contrast, a short-term decrease in blood leukocyte numbers represents a trafficking of cells out of the blood to target organs such as the skin (Dhabhar and McEwen, 1996) and lung (Kradin et al., 2001), or sites of immune activation (Dhabhar and
Conclusion
These studies take an important step towards comprehensively elucidating the kinetics, subpopulation specificity, and hormonal mechanisms mediating stress-induced changes in blood leukocyte distribution. To our knowledge these studies are the first to characterize and quantify numbers of specific immune cell populations and functional/maturation subtypes within the major leukocyte populations, during a complete time course of early and late changes induced by an acute or short-term stress
Role of funding source
Funding sources played no role in study design or any other process related to this manuscript except for providing the greatly-appreciated financial support.
Conflict of interest
The authors declare no conflicts of interest with regards to this manuscript.
Acknowledgments
We thank Maryse Aubourg for help with some of the experiments, and Sue Moseley for conducting the catecholamine assays. These studies and the writing of this manuscript would not have been possible without support from The John D. & Catherine T. MacArthur Foundation (BSM, FSD), The DeWitt Wallace Foundation Fellowship (FSD), The Dana Foundation (FSD), NIH grants AI48995, AR46299, CA107498, and startup support from the Carl & Elizabeth Naumann Fund (FSD).
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