Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress

Abstract

Dysregulation of innate immune responses has frequently been reported in stressassociated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c(+) dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6C(hi) monocytes and higher numbers of spleen-derived CD11b(+) cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45(hi) CD11b(+) cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2(+)) Ly6C(hi) monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6C(hi) monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.