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.Keywords: CD4 T cells r Chronic stress r Corticosterone r EAE Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt has been well established that stress may substantially affect the homeostatic regulation of the immune system [1][2][3]. In most Correspondence: Dr. Alon Monsonego e-mail: alonmon@bgu.ac.il animal models studied thus far, stressful triggers such as fear, maternal deprivation, social threat, or physiological challenge have been shown to induce immunosuppression associated with increased susceptibility to allergies and infectious diseases [1,4,5]. These effects are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, a complex network linking the nervous, endocrine and immune systems [6,7].The HPA axis can be triggered by stress or by proinflammatory cytokines (e.g. IL-1, IL-6, and TNF-α) to ultimately result in C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 758-769 Immunomodulation 759 the secretion of corticosterone (CORT) from the adrenal glands to the circulation [8]. CORT, in turn, acts to suppress the activation, proliferation, and trafficking of immune cells [9,10] and plays a role in autoimmune regulation via shifting from Th1/Th17 pro-inflammatory to Th2 antiinflammatory responses [11][12][13]. Indeed, previous studies have shown that rats producing lower CORT levels (e.g. due to genetic manipulation or adrenalectomy) are more susceptible to pathogenic autoimmunity [14]. CORT is therefore often used as an immunosuppressor in the clinical treatment of inflammatory and autoimmune diseases [9,15,16]. Regardless of the immunosuppressive effects of CORT, chronic exposure to stress has also been linked with relapse of autoimmune diseases such as multiple sclerosis [17,18] and psoriasis [19,2...

Effects of stress, acute alcohol treatment, or both on pre-pulse inhibition in high- and low-alcohol preferring mice

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“…Furthermore, this association only persisted among children born to mothers with low educational attainment at birth, which may suggest that factors such as lack of social or familial support or adequate coping mechanisms in these offspring may mediate the effects of bereavement. Chronic exposure to stress has been associated with destructive autoimmunity in mice, and also with a relapse of autoimmune diseases such as multiple sclerosis and psoriasis . Low levels of C‐peptide, a marker for low β cell function and an increased response to the diabetes‐associated autoantigens (GAD 65 , HSP60 and IA‐2) have also been observed among highly, and often chronically stressed children .…”