Repeated social defeat promotes persistent inflammatory changes in splenic myeloid cells; decreased expression of β-arrestin-2 (ARRB2) and increased expression of interleukin-6 (IL-6)

Abstract

Background: Previous studies suggest that persistent exposure to social stress in mammals may be associated with multiple physiological effects. Here, we examine the effects of social stress in rats, i.e. repeated social defeat, on behavior, hypothalamic-pituitary-adrenal (HPA)-axis and immune system. Methods: A resident-intruder paradigm, where an intruder rat was exposed to social stress by a dominant resident rat for 1 hour each day for 7 consecutive days was used. The day after the last stress exposure in the paradigm the data were analyzed. Variation in social interaction was observed manually, whereas locomotion was analyzed off-line by a purpose-made software. Gene expression in the pituitary gland, adrenal gland and myeloid cells isolated from the spleen was measured by qPCR. Results: The exposure to social stress induced decreased weight gain and increased locomotion. An increased nuclear receptor subfamily group C number 1 (NR3C1) expression in the pituitary gland was also shown. In myeloid cells harvested from the spleen, we observed decreased expression of the β 2-adrenergic receptor (ADRB2) and β-arrestin-2 (ARRB2), but increased expression of interleukin-6 (IL-6). Subsequent analyses in the same cells showed that ARRB2 was negatively correlated with IL-6 following the stress exposure. Conclusion: Our results show that that the experience of social stress in the form of repeated social defeat in rats is a potent stressor that in myeloid cells in the spleen promotes persistent inflammatory changes. Future research is needed to examine whether similar inflammatory changes also can explain the impact of social stress, such as bullying and harassment, among humans.

Workplace bullying increases the risk of anxiety through a stress-induced β2-adrenergic receptor mechanism: a multisource study employing an animal model, cell culture experiments and human data

“…However, long-term NE exposure causing receptor desensitization may diminish the suppressive effects (Hadcock and Malbon 1988). As previously shown, a reduced ADRB2 gene expression in stress-induced rats compared with control rats was demonstrated (Rajalingam et al 2020). Similarly, the NE and NE + DEX treated EL-1 cells-but not DEX treatment alone-showed reduced ADRB2 expression supporting the hypothesis that persistent NE exposure affects receptor responsivity.…”

“…The present study showed a clear association between reduced social interaction and increased level of circulating NE in rats previously exposed to repeated social defeat. Taken together with our recent observation that repeated social defeat induced a persistent decrease in the myeloid ADRB2 gene expression of the same stress-exposed animals (Rajalingam et al 2020), this suggests that exposure to ongoing and repeated social defeat may affect future social behavior in animals. Hence, our present in vivo and in vitro data point to a link between social stress, fear, social withdrawal, and NE-ADRB2 signaling.…”

“…As previously described (Rajalingam et al 2020), the stress conditioning was performed by temporarily removing the female rat one hour prior to introducing the intruder animal into the resident cage. The rats were separated upon social defeat (submissive supine posture, freeze, or flight) or after 10 min of interaction by a perforated plastic wall (Fig.…”

“…The social interaction test was conducted 1 day after the last stress exposure, i.e., 24 h after the last episode of defeat. As previously described (Rajalingam et al 2020), the test arena was a purpose made box (0.56 m 2 ) divided into three compartments by two gated plastic walls and a small wire-like container in each flanking compartment. The test rats were allowed to habituate in the center compartment for 4 min before a novel rat of the same strain was placed into one of the small wire-like containers.…”

Mapping of pituitary stress-induced gene regulation connects Nrcam to negative emotions

“…Previous findings suggest that environmental stressors, such as repeated social defeat (Jacobsen et al, 2020;Rajalingam et al, 2020), may be associated with fear and behavioral alterations (McKim et al, 2018;Wohleb et al, 2014). For example, repeated social defeat in social mammals triggers activation of subconscious parts of the brain, which in turn promotes nervousness (Rajalingam et al, 2021;Wohleb et al, 2014).…”