Toll-Like Receptor Signaling in Depression

Abstract

Depression is one of the most prevalent, disabling, and costly mental illnesses currently affecting over 300 million people worldwide. A subset of depressed patients display inflammation as indicated by increased levels of proinflammatory mediators in the blood and cerebrospinal fluid. Longitudinal and experimental studies suggest that this inflammatory profile may causally contribute to the initiation, maintenance, or recurrence of depressive episodes in the context of major depressive disorder (MDD). While the mechanistic pathways that mediate these depressogenic effects have not yet been fully elucidated, toll-like receptor (TLR) signaling is one potential common inflammatory pathway. In this review, we focus on the role that inflammation plays in depression, TLR signaling and its plasticity as a candidate pathway, its regulation by micro ribonucleic acids (miRNAs), and their potential as diagnostic biomarkers for identification of inflammatory subtypes of depression. Pre-clinical and clinical studies have demonstrated that TLR expression and TLR signaling regulators are associated with MDD. Further, TLR expression and signaling is in-turn, regulated in part by miRNAs and some TLR-responsive miRNAs indirectly modulate pathways that are implicated in MDD pathophysiology. These data suggest an intersection between TLR signaling regulation and MDD-linked pathways. While these studies suggest that miRNAs play a role in the pathophysiology of MDD via their regulatory effects on TLR pathways, the utility of miRNAs as biomarkers and potential treatment targets remains to be determined. Developing new and innovative techniques or adapting established immunological approaches to mental health, should be at the forefront in moving the field forward, especially in terms of categorization of inflammatory subtypes in MDD.

Keywords: Exosome; Inflammation; Major Depressive Disorder (MDD); TLR4; Toll-like Receptors (TLRs); miRNA.

Figure 1.. Toll-like Receptor PAMPs, DAMPs, and XAMPs.

Extracellular (1, 2, 4, 5, 6, 10) and intracellular (3, 7–9) toll-like receptors (TLRs) recognize a variety of pathogenic, self, and substances of abuse known as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and xenobiotics (XAMPs), respectively. Abbreviations: TIR-Toll-IL1-receptor domain, HSP-heat shock protein, grp94-glucose-regulated protein 94, HMGB1-high mobility group box-1, SAA-serum amyloid A, LPS-lipopolysaccharide, RSV-respiratory syncytial virus, LDL-low density lipoproteins, ATP-adenosine triphosphate, HIV-human immunodeficiency virus, ss-single stranded, ds-double stranded, CpG-cystine-phosphate-guanine, Mt-mitochondrial.

Figure 2.. Myd88- and TRIF-Dependent Toll Like-Receptor 4 Inflammatory Signaling.

Toll-like receptor 4 (TLR4) signaling is initiated upon LPS binding to the leucine-rich repeats located in the N-terminal domain. The MyD88 pathway is initiated upon recruitment of the MAL and MyD88 adapters to the C-terminal TIR domains, which leads to activation of downstream signaling proteins for transcription and activation of pro-inflammatory genes, such as TNF and IL-6. TLR4 is then endocytosed for within 30 minutes of LPS stimulation for initiation of the TRIF-dependent signaling through recruitment of the TRAM and TRIF adapters, leading to activation of cytoplasmic proteins and production of type I interferons, RANTES/CCL5, and IP-10. The TLR4/MD2/CD14-LPS receptor complex then undergoes a Rab7b-mediated lysosomal degradation or TLR4-mediated retrograde transport back to the plasma membrane. Abbreviations- Rantes: Regulated on Activation, Normal T Cell Expressed and Secreted, IP-10: IFNγ-inducible protein, NO: nitric oxide, ROS: reactive oxygen species, COX2: cyclooxygenase II enzyme.

Figure 3.. Human Toll-like Receptor Expression in the Central Nervous System.

Toll-like receptors (TLRs) are differentially expressed in each of the cell types located in the central nervous system (CNS). This figure depicts the putative expression of human TLRs in neurons, astrocytes, microglia, and oligodendrocytes.