Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder

Abstract

Activation of the inflammatory immune system provokes numerous neuroendocrine and neurotransmitter changes, many of which are similar to those provoked by physical or psychological stressors. These findings, among others, have led to the suggestion that the brain translates immune activation much as if it were a stressor. In this review, I provide synopses of the effects of traditional stressors on the release of corticotropin-releasing hormones at hypothalamic and extrahypothalamic sites, variations of serotonin and its receptors and changes of brain-derived neurotrophic factor (BDNF). These effects are similar to those elicited by activation of the inflammatory immune system, particularly the impact of the immune-signalling molecules interleukin-1 beta, interleukin-6, tumour necrosis factor-alpha and interferon-alpha on neuroendocrine, neurotransmitter and BDNF function. In addition, it is reported that stressors and cytokines may synergistically influence biological and behavioural processes and that these treatments may have long-term ramifications through the sensitization of processes associated with stress responses. Finally, I present an overview of the depressogenic actions of these cytokines in rodent models and in humans, and I provide provisional suggestions (and caveats) about the mechanisms by which cytokines and stressors might culminate in major depressive disorder.

Fig. 1: Working model showing potential routes by which stressors and cytokines could influence depressive state. Stressors and cytokines may promote several common neurochemical changes, and it is suggested that they may act synergistically in affecting some neurochemical processes. Moreover, stressors and cytokines may result in the sensitization of neurochemical processes, resulting in exaggerated responses to subsequent challenges. Both cytokines and stressors, as depicted in the figure, increase the release of corticotropin-releasing hormones (CRH) in hypothalamic and extrahypothalamic sites, although, in the case of stressors, this outcome may involve activation of bombesin-like peptides (neuromedin B and gastrin-releasing peptide). In addition to activating hypothalamic–pituitary–adrenal function, corticotropin-releasing hormones may influence serotonin (5-HT) processes, and γ-aminobutyric acid receptor A (GABA_A) activity may act as a mediator in this regard. The 5-HT variations (as well as those of other amines) may influence depression directly or may do so through other processes. In this regard, an alternative, although not necessarily mutually exclusive, pathway involves cytokine/stress activation of either nuclear factor-κB (NFκB), mitogen-activated protein (MAP) kinases or janus kinase / signal transducer and transcription (JAK-STAT) activator pathway signalling. These would influence oxidative or apoptotic mechanisms, leading to altered growth factor expression (e.g., brain-derived neurotrophic factor [BDNF]), again favouring impaired neuroplastic processes and culminating in major depression. ACTH = adrenocorticotropic hormone; AVP = arginine vasopressin; CORT = cortisol; DA = dopamine; GRP = gastrin-releasing peptide; IL = interleukin; NE = norepinephrin; NMB = neuromedin B; TNF = tumour necrosis factor. Reprinted from Anisman et al. Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 2008;85:1-74, with permission from Elsevier.