Toll-like receptors in chronic pain

Abstract

Proinflammatory central immune signaling contributes significantly to the initiation and maintenance of heightened pain states. Recent discoveries have implicated the innate immune system, pattern recognition Toll-like receptors in triggering these proinflammatory central immune signaling events. These exciting developments have been complemented by the discovery of neuronal expression of Toll-like receptors, suggesting pain pathways can be activated directly by the detection of pathogen associated molecular patterns or danger associated molecular patterns. This review will examine the evidence to date implicating Toll-like receptors and their associated signaling components in heightened pain states. In addition, insights into the impact Toll-like receptors have on priming central immune signaling systems for heightened pain states will be discussed. The influence possible sex differences in Toll-like receptor signaling have for female pain and the recognition of small molecule xenobiotics by Toll-like receptors will also be reviewed.

Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Toll-like receptor activation in astrocytes

Numerous TLRs are expressed and activated in astrocytes including TLRs 2, 3, 4, 5, 7, and 9. Several ligands have been found to activate certain TLRs in astrocytes including, but not limited to: lipoteichoic acid (LTA) (TLR2), soluble CD14 (TLR2), peptidoglycan (PGN) (TLR2, TLR4 TLR9), flagellin (TLR2, TLR4, TLR9), bacterial CpGs (TLR4, TLR5), high mobility group box-1 (HMGB1) (TLR2, TLR4), double-stranded RNA (dsRNA) (TLR3), lipopolysaccharide (LPS) (TLR4, TLR9) and Imiquimod (TLR7). Upon astrocytic TLR activation, numerous mediators are released, resulting in proinflammation. Such mediators include the proinflammatory cytokines: interleukin-6 (IL-6), interleukin-1alpha (IL-1α), tumor necrosis factor-alpha (TNF-α), IL-5, IL-13, IL-12p40, in addition to numerous proinflammatory mediators and chemokines: monocyte chemotactic protein-1 (MCP-1), reactive oxygen species (ROS), RANTES, interferon-beta (IFN-β), CXCL10, CCL5, inducible nitric oxide synthase (iNOS) and nitric oxide (NO). All TLRs, are known to signal via the MyD88 pathway excluding TLR3 which utilises the Toll/IL1 receptor (TIR) adaptor protein TRIF (Toll-receptor-associated activator of interferon), and TLR4 which can signal via both MyD88 and TRIF. Upon astrocytic TLR activation however, certain signalling components have been shown to be upregulated. TLR2 activation in astrocytes for example, has been demonstrated to utilise the co-receptor CD14. Furthermore, upon TLR4 activation, the TRIF-dependent pathway of TLR4 signalling has been shown to be inactive in astrocytes and utilizes the co-receptors MD-2 and CD14. (Bowman, et al., 2003; Bsibsi, et al., 2007; Bsibsi, et al., 2006; Butchi, et al., 2010; Carpentier, et al., 2005; El-Hage, et al., 2011; Jack, et al., 2005; Krasowska-Zoladek, et al., 2007).

Figure 2. Toll-like receptor activation in microglia

Several TLRs have been identified in microglial cells including TLRs 2, 3, 4, 7 and 9. Upon ligand recognition, these TLRs have been shown to release numerous proinflamamtory mediators, which play a role in chronic pain. Numerous ligands have been identified to activate certain TLRS in microglial cells including, but not limited to: endogenous danger signals such as heat shock proteins (HSPs) (TLR4) and high mobility group box-1 (HMGB1) (TLR4 and TLR2); lipopolysaccharide (LPS) (TLR4 and TLR2), peptidoglycan (PGN) (TLR2), double-stranded RNA (dsRNA) (TLR3), Imiquimod (TLR7) and bacterial CpGs (TLR9). Furthermore, numerous proinflamamtory cytokines have been shown to be released including interleukin-6 (IL-6), IL-18, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL1β), interleukin-1alpha (IL-1α), IL-12, IL-5, IL-13, IL-15; and proinflamamtory mediators including, but not limited to: superoxide anion (O2-), matrix metallopeptidase 9 (MMP-9), macrophage inflammatory protein-2 (MIP-2), inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclo-oxygenase 2 (COX-2), CCL3, CXCL2 and CXCL10. Upon microglial TLR activation, specific signalling components are activated. TLR4 activation in microglia for instance, has been shown to increase NFκB activation specifically and TLR3 receptor binding results in increased p38 MAPK activation. Moreover, the ATP receptors P2X4 and P2X7 have been located on microglial cells and ATP administration has demonstrated activity at P2X7 receptors in microglia, known to facilitate the release of IL-1β via the inflammasome complex. Furthermore, TLR2 receptor binding has demonstrated increased MyD88 activation including increased ERK, JNK, and NFκB activation. (Aravalli, et al., 2008; Butchi, et al., 2010; Chan et al., 2003; Kakimura, et al., 2002; Kielian et al., 2005; Mayer, et al., 2011; Suzuki, et al., 2004; Town, et al., 2006; Tsuda, et al., 2003; Wang, et al., 2000; Zhang et al., 2005)

Figure 3. Toll-like receptor expression and activation in dorsal root ganglion (DRG) and trigeminal ganglion neurons

Recent findings have demonstrated Toll-like receptor (TLR) expression and activation in human, murine and rodent DRG and/or trigeminal ganglion neurons. TLR 1, 2, 3, 4, 5, 6, 7 and 9 have been identified in DRG and/or trigeminal neurons. Challenge of certain DRG TLRs with their appropriate ligands including, double-stranded RNA (dsRNA) (TLR3), bacterial CpGs (TLR9), Gardiquimad (TLR7) and lipopolysaccharide (LPS) (TLR4), has resulted in the expression of proinflammatory mediators known to play a role in pathological pain. Moreover, LPS has also been identified to bind to receptors in trigeminal neurons. TLR 3, 7 and 9 stimulation in DRG neurons, results in increased release of prostaglandin E2 (PGE2) and calcitonin gene related peptide (CGRP) and the upregulation of CCL5, CXCL10, interleukin-1alpha (IL-1α) and interleukin-1beta (IL-1β) mRNA. In rat and mouse DRG neurons, LPS administration has also been demonstrated to increase the neuronal expression of tumor necrosis factor-alpha (TNF-α)receptors, specifically TNFR1, and also increases neuronal excitability. Furthermore, utilisation of TLR signalling co-receptors has also been identified in DRG neurons. TLR4 signaling in DRG neurons for example has been shown to utilize the diverse co-receptor MD-1. (Diogenes, et al., 2011; Hou and Wang, 2001; Li, et al., 2004; Ochoa-Cortes, et al., 2010; Qi, et al., 2011; Wadachi and Hargreaves, 2006; Xing et al., 2002).