Social stress alters splenocyte phenotype and function

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Abstract

Social stress of group-housed male mice induced a state of functional glucocorticoid (GC) resistance in splenocytes. The following studies examined the effects of paired-fighting (PF) stress on immune cell distribution and function in spleens of male mice. Following six daily PF stress sessions, splenic monocytes and neutrophils increased and lymphocytes decreased. PF also altered the distribution of CD62L and CD11b positive monocytes. Additionally, PF augmented proliferation and lowered the sensitivity of LPS-stimulated splenocytes to the antiproliferative effects of corticosterone, suggesting that PF induced a state of GC resistance in splenocytes. Together, these findings indicate that social stress altered phenotype and function of splenic immune cells. These findings may have implications for the healing of bite wounds that are often associated with social stress in rodents.

Introduction

A growing body of evidence indicates that social stress in rodents alters immune system function, and consequently, may affect susceptibility to infection or injury Barnard et al., 1993, Cohen et al., 1997, Padgett et al., 1998b, Quan et al., 2001, Sheridan et al., 2000. Stress-induced alterations in immune cell function may have been involved in modulating the effects of social stress on susceptibility. Indeed, it has been demonstrated that many types of chronic stress affected immune cell distribution and altered trafficking to the site of infection Dhabhar, 2000, Stefanski, 2000. Many of the immunosuppressive effects of stress were attributed to the effects of the glucocorticoid (GC) stress hormones Dhabhar and McEwen, 1999, Sheridan et al., 2000. In recent studies, we demonstrated that disruption of the social hierarchy in a cage of male mice (Social Disruption, SDR) altered splenocyte function. Specifically, introducing an aggressive intruder into a cage of male mice for six consecutive nights induced a state of functional glucocorticoid (GC) resistance in LPS-stimulated splenocytes. Viability of these splenocytes was higher in the presence of corticosterone compared to control cells Avitsur et al., 2001, Stark et al., 2001.

Several studies have demonstrated that social stress alters the distribution of immune cells in the thymus and blood Dreau et al., 1999, Stefanski, 2000. Initial observations from our laboratory showed that SDR increased the level of monocytes in the spleen (Avitsur et al., 2002). These findings suggest that the functional changes induced by SDR in splenocytes were accompanied by changes in the composition of immune cells in the spleen. Our findings further revealed an increase in the percentage of CD11b positive monocytes in SDR mice (Avitsur et al., 2002), suggesting that social stress altered the expression of adhesion molecules on splenocytes. The following studies sought to provide a more detailed analysis of the effects of social stress on splenocyte phenotype and function. Additionally, the specificity of these effects to SDR was examined. In this study, mice were repeatedly defeated by an aggressor in the paired-fighting (PF) stress paradigm. Following PF stress, spleens contained a higher number and percentage of monocytes, and a lower percentage of T cells. Furthermore, PF altered the distribution of CD62L and CD11b positive monocytes. PF also induced splenic GC resistance, indicating that this phenomenon was not exclusive to the SDR paradigm.

Section snippets

Animals

Subjects were male C57BL/6 mice (Charles River, Wilmington, MA) aged 7–10 weeks and housed four to five per cage. Animals were housed in an American Association for the Accreditation of Laboratory Animal Care (AAALAC) accredited facility. Mice were given free access to food and water and were maintained on a 12-h light/dark cycle (lights on at 6 AM). For the paired-fighting (PF) stress, aggressive mice were also used. Aggressors were singly housed C57BL/6 male mice selected on the basis of

Results

Control (n=5) and PF (n=8) mice were sacrificed on the morning after the sixth nightly PF cycle, their spleens were harvested and weighed, and single cell suspensions were obtained. The results show that PF induced splenomegaly (t(9)=−2.43, p<0.05, Fig. 1A) and increased the number of viable mononuclear cells (t(11)=−2.248, p<0.05, Fig. 1B).

Flow cytometry revealed that PF altered the composition of cells in the spleen. Specifically, PF significantly increased the number of monocytes and

Discussion

Repeated defeat by an aggressor in the PF stress paradigm altered the phenotype and function of spleen cells. Six daily PF encounters resulted in splenomegaly and an increase in the total number of mononuclear cells in the spleen. Flow cytometry revealed that this increase in cell numbers was mainly due to an increase in the number of monocytes (a nearly three-fold increase). Additionally, a small yet significant increase in the number of splenic neutrophils was detected (less than a two-fold

Acknowledgements

The authors thank Patty A. Guerra, John Hunzeker, Kari A. Kramer and Alison Saul for their excellent help. This study was supported by NIH grants MH46801-08 (JFS), DE13749-01 (JFS), AI 48995 (FSD) and the Dana Foundation (FSD).

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