A critical review of human endotoxin administration as an experimental paradigm of depression

Abstract

The syndrome called depression may represent the common final pathway at which different aetiopathogenic processes converge. One such aetiopathogenic process is innate immune system activation. Some depressed patients have increased levels of inflammatory cytokines and other immunologic abnormalities. It is not known whether immune system activation contributes to the pathogenesis of depressive symptoms. Supporting this possibility is the observation that in both rodents and humans, exogenous immune stimuli such as endotoxin can produce symptoms that resemble depression. A new approach to depression research would be to use immune stimuli to elicit depressive symptoms in humans. Here we review each of the symptoms elicited in humans by endotoxin administration, and compare this model to two other immune depression paradigms: interferon-alpha treatment and typhoid vaccine administration, to assess to what degree endotoxin administration represents a valid model of immune depression. We also review corresponding behavioral changes in rodents and the potential molecular pathways through which immune system activation produces each symptom.

Conflict of interest statement

Disclosure/Conflict of Interest: Neither N.D. nor J.H. has received any income or financial support from any entity, or has any personal financial holdings, that could be perceived as a potential conflict of interest.

Figures

Figure 1

Endotoxin binds to CD14 and Toll-like receptor 4 (TLR4) on the surface of monocytes and endothelial cells. The TLR4 associated Toll-IL-1-receptor domain (TIR) binds to myeloid differentiation factor 88 (MyD88), which, through various intermediate steps, leads to the activation of nuclear factor κB (NFκB). This transcription factor initiates the transcription of various inflammatory mediators, including tumor necrosis factor (TNF), interleukin-1 converting enzyme (ICE) which converts pro-IL-1 into bioactive IL-1, cyclooxygenase-2 (COX-2)which converts arachidonic acid into prostanoids such as prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS) which produces nitric oxide. The MyD88-dependent pathway can also be activated by IL-1 and TNF signaling through their cognate receptors. The MyD88-independent pathway leads to the transcription of interferon-β (IFN-β).

Figure 2

Pathways through which inflammatory stimuli produce sickness behavior and depressive-like symptoms. Endotoxin administered intraperitoneally (i.p.) or intravenously (i.v.) is detected by leukocytes, causing the release of inflammatory cytokines, including IL-1 and TNF. When endotoxin is administered i.p., inflammatory cytokines released in the abdominal cavity signal to the brain via afferent fibers of the vagus nerve. When endotoxin is administered i.v., inflammatory cytokines released in the blood signal to the brain through receptors on endothelial cells. Endotoxin can also signal directly through endothelial cells when administered i.v. In the brain, peripheral inflammatory signals lead to local production of inflammatory mediators and sickness behavior. Administration of inflammatory signals to the brain, including endotoxin and IL-1, also leads to peripheral release of inflammatory mediators, highlighting the complexity of brain-immune interactions.