Effects of repeated social stress on leukocyte distribution in bone marrow, peripheral blood and spleen
Introduction
Leukocytes continuously circulate in blood and lymph between the various body compartments. This process of immune cell trafficking has an important surveillance function that ensures the detection of antigen and enables the immune system to generate a rapid and effective response. The regulation of leukocyte trafficking is, apart from immunological mechanisms, mainly under control of the autonomous nervous system and the endocrine system (Ottaway and Husband, 1994). Behavioral and environmental challenges that are associated with either transient or chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) have been repeatedly shown to alter both the functional capacities and the migration pattern of immune cells in the body Dhabhar et al., 1995, McEwen et al., 1997, Stefanski, 2000, Stefanski and Engler, 1999. Recent studies from our laboratory demonstrated that repeated social defeat in male mice was associated with decreased glucocorticoid receptor (GR) mRNA expression in the brain, elevated plasma concentrations of corticosterone, interleukin-6 and nerve growth factor (NGF) as well as the appearance of large numbers of neutrophils, monocytes and B cells in the murine spleen Avitsur et al., 2001, Avitsur et al., 2002, Quan et al., 2001, Stark et al., 2001. The increase in splenic leukocytes resulted not only in an enlargement of the spleen, but was also accompanied by alterations in the sensitivity of the cells to the inhibitory action of glucocorticoids (GC) in vitro. Lipopolysaccharide (LPS)-stimulated splenocytes from male mice that repeatedly experienced acute encounters with an aggressive conspecific exhibited considerably higher cell survival in presence of physiological and pharmacological concentrations of corticosterone than GC-treated splenocyte cultures from controls Avitsur et al., 2001, Stark et al., 2001. Importantly, these socially defeated animals were also more susceptible to endotoxic shock after in vivo challenge with bacterial LPS (Quan et al., 2001). Cellular depletion studies revealed that the stressor-induced decrease in GC sensitivity of immune cells in the spleen was dependent on the presence of CD11b+ (Mac-1) leukocytes but not B cells (Stark et al., 2001). Investigation of the molecular mechanisms underlying the functional GC resistance in the spleen of repeatedly defeated mice revealed not only reduced GR mRNA expression but also impaired nuclear translocation of the GR and lack of transcriptional suppression of the nuclear transcription factor NF-κB in CD11b+ leukocytes Quan et al., 2001, Quan et al., 2003.
The origin of the glucocorticoid-insensitive CD11b+ leukocytes in the spleen remains unclear. In contrast to the neonatal mouse spleen, the adult murine spleen exhibits only low myelopoietic activity and has limited potential to generate myeloid cells in response to proliferative stimuli such as colony-stimulating factors (Wolber et al., 2002). Like in most other adult mammals, the major proportion of murine granulocytes and monocytes is generated in the bone marrow which is also the major source of B cells. Acute and chronic social stress has been shown to result in neutrophilia and monocytosis in the blood of subordinate animals, and it was proposed that the cellular alterations in the blood may reflect the trafficking of immune cells between lymphoid organs Stefanski, 2000, Stefanski and Engler, 1998, Stefanski and Engler, 1999. Therefore, we hypothesized that the repeated neuroendocrine activation in socially defeated mice causes the mobilization of neutrophils, monocytes and B cells in the bone marrow and leads to the redistribution of these cells via the circulation to the spleen. To test this hypothesis, we simultaneously assessed the distribution pattern of the major leukocyte and lymphocyte subpopulations in the bone marrow, peripheral blood and spleen of socially defeated mice after 2, 4 and 6 days of recurrent stressor exposure and compared the results with unchallenged controls. Since short and rapid reversible leukocyte fluctuations in response to an acute stressor exposure can mask the more persistent alterations in leukocyte redistribution, we decided to determine the cell distribution 12 h after termination of the social confrontation.
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Experimental animals
Inbred male C57BL/6 mice, aged 6–8 weeks, were purchased from Charles River Laboratories (Wilmington, MA) and were housed three animals per cage in a facility accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC). Mice had ad libitum access to food and water and were kept under environmentally controlled conditions on a 12:12-h light/dark cycle (lights off at 6:00 p.m.). Animals were allowed to acclimate to the new surroundings for 2 weeks before
Effects of repeated social defeat on leukocyte counts
Repeated social defeat markedly altered the distribution of leukocytes in bone marrow, peripheral blood and spleen (Table 1). In the bone marrow, total leukocyte numbers showed a significant drop after 2 days of social disruption (SDR) and remained decreased after 4 and 6 days of recurrent stressor exposure when compared to control mice (ANOVA: F[3,50]=8.84, p<0.001). However, after the initial decrease in bone marrow cellularity, a slight increase in total leukocyte counts was evident in the
Discussion
The distribution of leukocytes throughout the body is critical to the efficiency of the immune system. The results of the present study demonstrate that repeated social defeat was associated with a major redistribution of immune cells between the bone marrow, peripheral blood and spleen.
Acknowledgments
The authors thank Kari A. Kramer for excellent technical assistance. This work was supported by a grant from the National Institute of Mental Health to J.F.S (RO1 MH46801).
References (49)
- et al.
Social stress induces glucocorticoid resistance in subordinate animals
Horm. Behav.
(2001) - et al.
Social stress alters splenocyte phenotype and function
J. Neuroimmunol.
(2002) - et al.
Animal models of social stress: effects on behavior and brain neurochemical systems
Physiol. Behav.
(2001) - et al.
Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease
Brain Behav. Immun.
(2003) - et al.
Further evidence for behaviorly induced hypoxic conditions in subordinate mice
Comp. Biochem. Physiol. A
(1984) - 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.
Social stress and T cell maturation in male rats: transient and persistent alterations in thymic function
Psychoneuroendocrinology
(2003) - et al.
Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species
Blood
(1998) - et al.
Formation of a new social group of unfamiliar female rhesus monkeys affects the immune and pituitary adrenocortical systems
Brain Behav. Immun.
(1991) - et al.
Altered T-lymphocyte response following aggressive encounters in mice
Physiol. Behav.
(1990)
Flow cytometric identification of murine neutrophils and monocytes
J. Immunol. Methods
Glucocorticoids inhibit apoptosis of human neutrophils
Blood
Examination of the neuroendocrine basis for the social conflict-induced enhancement of immunity in mice
Physiol. Behav.
The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions
Brain Res. Brain Res. Rev.
The influence of neuroendocrine pathways on lymphocyte migration
Immunol. Today
Social stress increases the susceptibility to endotoxic shock
J. Neuroimmunol.
Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice
J. Neuroimmunol.
Modulation of neutrophil apoptosis by psychological stress and glucocorticoid
Int. J. Immunopharmacol.
Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels
Psychoneuroendocrinology
Social stress in laboratory rats: hormonal responses and immune cell distribution
Psychoneuroendocrinology
Social stress in laboratory rats: behavior, immune function, and tumor metastasis
Physiol. Behav.
Effects of acute and chronic social stress on blood cellular immunity in rats
Physiol. Behav.
Social stress, dominance and blood cellular immunity
J. Neuroimmunol.
Long-term colony housing in Long Evans rats: immunological, hormonal, and behavioral consequences
J. Neuroimmunol.
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