title: Chronic exposure to stress predisposes to higher autoimmune susceptibility in C57BL/6 mice: glucocorticoids as a double-edged sword.
abstract: Stress activates the hypothalamic-pituitary-adrenocortical axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL/6 mice. Under baseline (nonstressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift toward proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4(+) CD25(+) Treg cells. This demonstrates that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.
authors.affiliation: Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Idan
authors.initials: I
authors.lastname: Harpaz
authors.forename: Shai
authors.initials: S
authors.lastname: Abutbul
authors.forename: Anna
authors.initials: A
authors.lastname: Nemirovsky
authors.forename: Ram
authors.initials: R
authors.lastname: Gal
authors.forename: Hagit
authors.initials: H
authors.lastname: Cohen
authors.forename: Alon
authors.initials: A
authors.lastname: Monsonego
mesh_terms: D000818:Animals; D001007:Anxiety; D015551:Autoimmunity; D003345:Corticosterone / Q000276:immunology / Q000494:pharmacology; D004198:Disease Susceptibility / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000502:physiology; D013312:Stress, Physiological / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D005938:Glucocorticoids; D003345:Corticosterone