Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine

Abstract

The spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain-spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.

A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration

“…Recently, we observed marked increases in spleen weight in CSDS-susceptible mice compared with non-CSDS control mice and CSDS-resilient mice 26 . In addition, McKim et al 51 reported that the total increase in the number of splenic erythrocytes, monocytes, and granulocytes derived from splenic progenitors that migrated from the bone marrow is associated with an increase of about twofold in the size and weight of the spleen after chronic stress.…”

“…Recently, we reported that levels of colony stimulating factor 1 receptor (CSF1R) in the spleen, but not postmortem brain, from patients with depression were significantly lower than those of control groups, and that there was a negative correlation between CSF1R and interacting protein SPI1 in the spleen 57 , suggesting a brain-spleen axis in psychiatric disorders such as depression 26,57,58 . A recent study demonstrated that neurons in the central nucleus of the amygdala and the paraventricular nucleus that express corticosteronereleasing hormone are connected to the splenic nerve, indicating a key role of brain-spleen communication in antibody production 59 .…”

“…The spleen, which is a large immune organ, plays an essential role in systemic immune function. Recently, we demonstrated a notable increase in splenic size and weight in CSDS-susceptible mice compared with non-CSDS control mice and CSDS-resilient mice 26 , suggesting a role for the brain-spleen axis in stress-induced depression.…”

“…The bilateral mPFC was collected rapidly and stored at −80°C until bioanalysis. The weight of spleens was recorded immediately after spleen removal 26 .…”

Immunoregulation and antidepressant effect of ketamine

“…Recently, research had found that the brain–spleen axis might contribute to the pathogenesis of depression [ 91 ]. In mice model of chronic social defeat stress (CSDS), natural killer group 2, member D (NKG2D) expression in the spleen, splenic volume, and weight in CSDS-susceptible mice were higher than that of control mice and CSDS-resilient mice.…”