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 lipopolysaccharide (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 LPS and BCG-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 hepatitis 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.

Figure 1

Time-dependent dissociation of sickness and depressive-like behaviors. Acute sickness is induced following induction of proinflammatory cytokines in the brain. IDO is activated by these proteins, which leads to the induction of depressive-like behavior at a later point in time.

Figure 2

An emerging view of alcohol abuse, the immune system and behavior. Chronic ingestion of alcohol leads to both systemic and neuroinflammation by activating TLR4. Systemically, this occurs on Kupffer cells in the liver sinusoids and in the brain it occurs by activation of TL4 on microglia and astrocytes. Chronic alcohol consumption is likely to prime Kupffer cells so that they synthesize and release enhanced amounts of IL-6, TNFα into the circulation. Activity of the enzyme 2, 3 tryptophan dioxygenase (TDO) is also increased. Similarly, hepatocytes synthesize greater amounts of C-reactive protein and there is an increase in oxidation of polyunsaturated fatty acids. In the brain, chronic alcohol consumption somehow leads to activation of TLR4, perhaps by causing the release of damage-associated molecular patterns such as high-mobility group box 1 (HMGB1) which subsequently binds TLR4. Downstream signaling pathways are activated, such as NFκβ, and microglia express chemotactic proteins such as CCL2 (MCP-1) that can attract monocytes into the CNS. Proinflammatory cytokines such as interferon-α and TNFα are synthesized, which may cause an increase in expression of indoleamine 2, 3 dioxygenase (IDO). The downstream tryptophan metabolites of IDO are likely to cause functional changes in neuronal circuits that culminate in inflammation-associated changes in mood, such as depression.

Figure 3

A conceptual model of the role for neuroinflammation in cognition (Section A on abscissa) as extended to mood changes caused by alcohol consumption. Low amounts of proinflammatory cytokines such as found in IL-1 receptor-deficient animals reduce learning and memory (section B on the abscissa). An optimal amount of cytokines is required for beneficial effects on cognition, and similar effects may occur with the effect of moderate alcohol consumption on mood. However, if proinflammatory cytokines increase to excessive levels in the CNS as caused by chronic alcohol consumption, learning and memory as well as depressive-like behavior can occur (part C on abscissa). Although enhanced excitability of glutamatergic signals seldom leads to epileptic-like seizures, a further elevation in brain inflammation can lead to neuronal death (section C). Figure from (Yirmiya and Goshen, 2011), with permission.