Stress-related immunosuppression and opioid-dependent Fas expression

Abstract

Yin, D. et al. (2000) Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression. J. Exp. Med. 191, 1423–1428Enhanced susceptibility to infection has long been linked to psychological or physical stress. It is accepted that stressors induce the release of hormones and neurotransmitters; now, Yin et al. describe a direct mechanism by which stress affects immune responses. Using a model in which mice were subjected to chronic physical restraint over 48 hours, they show that the number of splenocytes in stressed animals is significantly reduced. Not only is this process directly related to an increase in CD95 (Fas/APO-1) expression, but it seems to be dependent on the activity of endogenous opioids.When subject to physical restraint for two 12-hour periods over two days, BALB/c mice developed severe reduction in splenic lymphocyte numbers: a decrease of 30–45% compared with unstressed controls. The loss of lymphocytes was correlated with increased apoptosis, as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. In parallel, it was shown that expression of CD95, but not CD95-ligand (CD95L) was increased in splenocytes from stressed animals, and that blocking CD95–CD95L interactions diminished cell loss. The stress-induced changes in CD95 expression and lymphocyte number could also be blocked by the opioid receptor antagonists naltrexone or naloxone. Strikingly, the reduction of splenocytes in this model system seems to be independent of the hypothalamo-pituitary-adrenal (HPA) axis, as both adrenalectomized and sham-operated mice exhibited similar responses to chronic stress.This paper makes an important contribution to our understanding of the neuroimmunology of stress, demonstrating that the stress-dependent release of endogenous opioids can directly and rapidly suppress the immune system through CD95-mediated apoptosis. The next step will be to identify the specific opioid receptor types involved, and their detailed role in connecting neural and immunological systems.