Relationship between hypothalamic-pituitary-adrenocortical axis reactivity and innate immunity in mice

Introduction:

The immune system and the hypothalamic-pituitary-adrenocortical (HPA) axis affect each other in a bidirectional relationship. Inflammatory responses activate the HPA axis and in contrast, glucocorticoids released from the adrenal cortex suppress immune activity. In patients suffering from stress-associated affective disorders such as major depression, however, dysregulations of both, the immune system and the HPA axis have frequently been reported. The aim of the current study was to assess how genetic predisposition for extremes in HPA axis reactivity affected basal and ex vivo lipopolysaccharide (LPS)-stimulated innate immune cell composition as well as corticosterone (CORT) sensitivity in mice.

Methods:

Mice selectively bred for high, intermediate, or low reactivity (HR, IR, LR) of the HPA axis (CORT release in response to stressors) were sacrificed at 6 months of age and spleens were dissected. Splenocytes were isolated, cultured overnight either with or without LPS, stained, and analyzed by flow-cytometry. In addition, viability of cells was assessed after stimulation with LPS and exposure to increasing concentrations of CORT.

Results:

HR mice showed decreased numbers of CD11b+ myeloid cells as well as CD11c+ MHC class II+ dendritic cells (DCs) compared to IR mice while numbers of cytokine producing myeloid cells and DCs were not changed. LR mice, in contrast, presented increased numbers of CD11b+ myeloid cells producing the pro-inflammatory cytokine tumor necrosis factor (TNF) as well as the anti-inflammatory cytokine interleukin (IL)-10 compared to IR mice. In addition, LR mice had significantly higher numbers of CD11b+ myeloid cells after LPS stimulation. LPS-stimulated splenocytes of LR mice also showed a lower sensitivity to CORT than those of the other lines.

Conclusion:

These data suggest an increased activation of the innate immune response already under basal conditions in mice with low HPA axis reactivity. In addition to lower CORT levels over the diurnal cycle, reduced sensitivity to the immunosuppressive effects of CORT might contribute to this phenotype. Further studies will address the effects of acute and chronic stress on behavior and immune responses in these mouse lines, adding to the understanding of the interplay between stress, HPA axis activity, immune response, and behavior.