Alcoholism and inflammation: Neuroimmunology of behavioral and mood disorders

Abstract

Alcohol abuse changes behavior and can induce major mood disorders such as depression. Recent evidence in pre-clinical rodent models and humans now supports the conclusion that the innate immune system is an important physiological link between alcoholism and major depressive disorders. Deficiency of toll-like receptor 4 (TLR4), a protein that has been known to immunologists for 50 years, not only prevents lipopolysaccaride (LPS)-induced sickness behavior but recently has been demonstrated to induce resistance to chronic alcohol ingestion. Activation of the immune system by acute administration of LPS, a TLR4 agonist, as well as chronic infection with Bacille Calmette-Guérin, (BCG) causes development of depressive-like behaviors in pre-clinical rodent models. Induction of an enzyme expressed primarily in macrophages and microglia, 2,3 indoleamine dioxygenase, shunts tryptophan catabolism to form kynurenine metabolites. This enzyme is both necessary and sufficient for expression of inflammation-induced depressive-like behaviors in mice. New findings have extended these concepts to humans by showing that tryptophan catabolites of 2,3 indoleamine dioxygenase are elevated in the cerebrospinal fluid of cancer patients treated with the recombinant cytokine interferon-α. The remarkable conservation from mice to humans of the impact of inflammation on mood emphasizes the ever-expanding role for cross-talk among diverse physiological symptoms that are likely to be involved in the pathogenesis of alcohol abuse. These findings present new and challenging opportunities for scientists who are engaged in brain, behavior and immunity research.

Role of microglia in CNS inflammation

“…In our opinion, the terms neuroinflammation and microglial inflammation are being applied so widely and so uncritically that they have effectively lost their meaning. Recent additions to the ''inflammation spectrum'' of brain disease include epilepsy [59], neurogenesis [60], obesity in mood disorders [61], and alcoholism [62]. While inflammation in the CNS does employ some of the same molecules and processes that occur in both peripheral local and systemic inflammation, the presence of these molecules per se should not be considered as inflammation of brain tissue [62].…”

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…Multiple sclerosis is the prototypical neuroinflammatory disease (1); however, a role for the immune system has been proposed in the pathogenesis of several other CNS diseases including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, epilepsy, depression, and addictive disorders (2)(3)(4)(5)(6)(7)(8). Loss of neurons or impairment of neuronal function underlying these diseases may be caused or exacerbated by neuroinflammation, which results from chronic activation of microglia, the primary immune surveillance cells of the brain.…”

Serum brain-derived neurotrophic factor levels in relation to comorbid depression and cytokine levels in Nepalese men with alcohol-use disorders

“…In particular, raised circulatory concentrations of inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) are reported in depression (Dowlati et al, 2010;Irwin & Miller, 2007;Liu, Ho, & Mak, 2012). Increased inflammatory markers are also observed in AUD (Crews et al, 2006;Kelley & Dantzer, 2011;Szabo & Mandrekar, 2009), and in the context of MD in AUD patients (Schleifer, Keller, & Czaja, 2006). We have recently reported that AUD inpatients with a positive history of MD, rather than recent depression, had higher inflammatory cytokine levels, which appeared to be modulated by AUD severity .…”