Social stress alters splenocyte phenotype and function
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).
References (18)
- et al.
Social stress induces glucocorticoid resistance in subordinate animals
Horm. Behav.
(2001) - et al.
Social disruption induced glucocorticoid resistance: kinetics and site specificity
J. Neuroimmunol.
(2002) - et al.
Effect of social conflict on immune responses and E. coli growth within closed chambers in mice
Physiol. Behav.
(1999) - et al.
Integrin signaling and cell growth control
Curr. Opin. Cell Biol.
(1998) - et al.
Restraint stress slows cutaneous wound healing in mice
Brain Behav. Immun.
(1998) - et al.
Integrins take partners: cross-talk between integrins and other membrane receptors
Trends Cell Biol.
(1998) - et al.
Social stress increases the susceptibility to endotoxic shock
J. Neuroimmunol.
(2001) - et al.
Interleukin-6 and the development of social disruption-induced glucocorticoid resistance
J. Neuroimmunol.
(2002) Social stress in laboratory rats: hormonal responses and immune cell distribution
Psychoneuroendocrinology
(2000)
Cited by (79)
IL-1 Receptor-1 on Vglut2<sup>+</sup> neurons in the hippocampus is critical for neuronal and behavioral sensitization after repeated social stress
2022, Brain, Behavior, and Immunity - HealthCitation Excerpt :All procedures were in accordance with the NIH Guidelines and were approved by the Ohio State University Institutional Laboratory Animal Care and Use Committee. Social Defeat: Mice were subjected to a modified version of repeated social defeat as previously described (Avitsur et al., 2002, 2003; DiSabato et al., 2021). In brief, experimental mice were placed individually into the cages of CD-1 aggressor mice for up to 1h (between 16:00 to 18:00) per night for six consecutive nights.
Distinct immune and transcriptomic profiles in dominant versus subordinate males in mouse social hierarchies
2022, Brain, Behavior, and ImmunitySplenic Denervation Attenuates Repeated Social Defeat Stress-Induced T Lymphocyte Inflammation
2021, Biological Psychiatry Global Open ScienceThe role of physical trauma in social stress-induced immune activation
2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :At the end of each session, all PF mice are returned to their respective home cage and group-housed until the next PF session starts. In a respective control session, group-housed control animals were removed from their home cage and housed individually for 30 min in a laboratory cage without being exposed to an aggressor male (Avitsur et al., 2002b). In contrast to PF, the experimental setup of the SRO paradigm requires the establishment of stable social hierarchies within colonies of group-housed male mice.