Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

Abstract

Major depressive disorder (MDD) and other mood disorders remain difficult to effectively treat, and innovative interventions and therapeutic targets are needed. Psychological stressors and inappropriate inflammation increase the risk and severity of mood disorders; however, only recently have the importance of sterile inflammatory processes in this effect been revealed. This review will introduce the reader to pathogen vs sterile inflammation, inflammatory receptor-ligand interactions, microbial-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and the more recent discovery of the role of the inflammasome in peripheral and central nervous system cytokine/chemokine inflammatory responses. The review will focus on current preclinical and clinical evidence that sterile inflammation and inflammasome-dependent signaling may contribute to mood disorders. By understanding these inflammatory signaling processes, new approaches for quieting chronic or inappropriate inflammatory states may be revealed and this could serve as novel pharmacological targets for the treatment of mood disorders.

Figure 1

Substantial overlap between pathogen-associated molecular pattern (PAMP) and stress-evoked, likely danger-associated molecular pattern (DAMP), inflammatory protein changes. This schematic is based on results from a series of studies measuring inflammatory proteins in blood and peripheral tissues (spleen, liver) using multiplex enzyme-linked immunosorbent assays (ELISAs) and mRNA using quantitative real-time PCR (qRT-PCR) after lipopolysaccharide (LPS) (PAMP) or tailshock.

Figure 2

The previously unpublished results of a study testing the effect of a psychological stressor, predatory order, on danger-associated molecular pattern (DAMPs) in the blood. Adult, male Sprague–Dawley rats (8 per group) had towels placed in their home cages that were saturated either with neutral control odor (strawberry) or a predatory odor (ferret urine) 10 min per day for 7 days. Serum levels of heat-shock protein 72 (Hsp72) were measured using enzyme-linked immunosorbent assay (ELISA).

Figure 3

Both single signal (inflammasome-independent) and double signal (inflammasome-dependent) sterile inflammation. Inflammasome-dependent cytokine synthesis and release is a two-step process that is initiated after ligation of Toll-like receptor (TLRs) and other receptors capable of binding danger-associated molecular patterns (DAMPs) and/or microbial-associated molecular patterns (MAMPs) leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain protein 3) gene transcription, translation, and protein production (Duewell et al, 2010). Once sufficient NLRP3 protein has been formed, then a second activation signal is needed that leads NLRP3 to interact with the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which then recruits procaspase-1 through its caspase recruitment domain. This assembly of proteins is considered the inflammasome, and once formed triggers the activation/cleavage of procaspase 1. Mature, active caspase-1 then acts to cleave pro-interleukin-1β (IL-1β) into mature IL-1β (and IL-18) protein. The NLRP3 inflammasome responds to a broad range of signals, for example, ATP, K+ efflux, β-amyloid, silica, uric acid crystals, and reactive oxygen species (ROS) (Elliott and Sutterwala, 2015). In addition, there are several candidate receptors capable of binding DAMPs and MAMPs, including TLRs, RAGE, and CD91 (Asea et al, 2002; Calderwood et al, 2007a, b). This figure was adapted from a figure courtesy of Tom Maslanik, PhD/MBA.

Figure 4

A model of stress-induced sterile inflammatory processes in the brain and the neural impact of these processes. We propose that exposure to stressors results in the release of danger-associated molecular patterns (DAMPs) within the brain, presumably from damaged or dying neurons. These neuron-derived DAMPs then target their cognate receptors on microglia leading to inflammasome activation and the synthesis and secretion of interleukin-1β (IL-1β). The secreted form of IL-1β may drive the induction of indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan into kynurenine and thereby reduces the available pool of tryptophan for serotonin (5-HT) synthesis. Reductions in 5-HT synthesis may then mediate, in part, the effects of stress on sickness behavior.