Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 45; pp. 16136 - 16141
• Main Authors: Hodes, Georgia E., Pfau, Madeline L., Leboeuf, Marylene, Golden, Sam A., Christoffel, Daniel J., Bregman, Dana, Rebusi, Nicole, Heshmati, Mitra, Aleyasin, Hossein, Warren, Brandon L., Lebonté, Benoit, Horn, Sarah, Lapidus, Kyle A., Stelzhammer, Viktoria, Wong, Erik H. F., Bahn, Sabine, Krishnan, Vaishnav, Bolaños-Guzman, Carlos A., Murrough, James W., Merad, Miriam, Russo, Scott J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.11.2014; National Acad Sciences
• Subjects: Allografts; Animals; Anxiety; Anxiety Disorders - genetics; Anxiety Disorders - immunology; Anxiety Disorders - pathology; Behavior, Animal; Biological Sciences; Bone marrow; Bone Marrow Transplantation; brain; Chimeras; Cytokines; Depressive disorders; Disease Susceptibility - immunology; Disease Susceptibility - pathology; Emotions; Immune system; inflammation; interleukin-6; Interleukin-6 - genetics; Interleukin-6 - immunology; Leukocytes; Major depressive disorder; Mental depression; Mice; Mice, Knockout; Monoclonal antibodies; Phenotypes; Psychological stress; psychosocial factors; Rodents; Social interaction; Stress; stress response; Stress, Psychological - genetics; Stress, Psychological - immunology; Stress, Psychological - pathology; Time Factors; Transplantation Chimera - genetics; Transplantation Chimera - immunology; anxiety; stress; leukocytes; depression; interleukin-6
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1415191111

Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6 ⁻/⁻) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6 ⁻/⁻ BM chimeric and IL-6 ⁻/⁻ mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities. Significance Depression and anxiety have been linked to increased inflammation. However, we do not know if inflammatory status predates onset of disease or whether it contributes to depression symptomatology. We report preexisting individual differences in the peripheral immune system that predict and promote stress susceptibility. Replacing a stress-naive animal’s peripheral immune system with that of a stressed animal increases susceptibility to social stress including repeated social defeat stress (RSDS) and witness defeat (a purely emotional form of social stress). Depleting the cytokine IL-6 from the whole body or just from leukocytes promotes resilience, as does sequestering IL-6 outside of the brain. These studies demonstrate that the emotional response to stress can be generated or blocked in the periphery, and offer a potential new form of treatment for stress disorders.