title: Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress.
abstract: 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.
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Georgia E
authors.initials: GE
authors.lastname: Hodes
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Madeline L
authors.initials: ML
authors.lastname: Pfau
authors.affiliation: Departments of Gene and Cell Medicine, Oncological Sciences, and.
authors.forename: Marylene
authors.initials: M
authors.lastname: Leboeuf
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Sam A
authors.initials: SA
authors.lastname: Golden
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Christoffel
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Dana
authors.initials: D
authors.lastname: Bregman
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Nicole
authors.initials: N
authors.lastname: Rebusi
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Mitra
authors.initials: M
authors.lastname: Heshmati
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.affiliation: Department of Psychology, Florida State University, Tallahassee, FL 32306-4301;
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Warren
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Benoit
authors.initials: B
authors.lastname: Lebonté
authors.affiliation: Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Sarah
authors.initials: S
authors.lastname: Horn
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Lapidus
authors.affiliation: Institute of Biotechnology, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, United Kingdom; Department of Neuroscience, Erasmus Medical Center, NL 3000 CA Rotterdam, The Netherlands;
authors.forename: Viktoria
authors.initials: V
authors.lastname: Stelzhammer
authors.affiliation: CNS-Pain Innovative Medicine Unit, External Science, AstraZeneca Pharmaceuticals, Wilmington, DE 19850; and.
authors.forename: Erik H F
authors.initials: EH
authors.lastname: Wong
authors.affiliation: Institute of Biotechnology, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, United Kingdom; Department of Neuroscience, Erasmus Medical Center, NL 3000 CA Rotterdam, The Netherlands;
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Department of Psychology, Florida State University, Tallahassee, FL 32306-4301;
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bolaños-Guzman
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: James W
authors.initials: JW
authors.lastname: Murrough
authors.affiliation: Departments of Gene and Cell Medicine, Oncological Sciences, and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; scott.russo@mssm.edu.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
mesh_terms: D064591:Allografts; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001522:Behavior, Animal; D016026:Bone Marrow Transplantation; D004198:Disease Susceptibility / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013315:Stress, Psychological / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology
chemical_list: D015850:Interleukin-6
keywords: anxiety; depression; interleukin-6; leukocytes; stress