Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway

Abstract

Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation. TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria. Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene. Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases. This implies that drugs or substances that modify these pathways may prevent or improve the abovementioned diseases. Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6-shogaol, cinnamon extract, N-acetylcysteine, melatonin, and molecular hydrogen. The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many "civilization" disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders.

Fig. 1

Toll-like receptor (TLR) activation. Toll-like receptors TLR2 and TLR4 are part of the innate immune system. Both recognize primary bacterial components, i.e., TLR2 recognizes lipoproteins and TLR4 lipopolysaccharides (LPS). TLR activation occurs through receptor dimerization. TLR4 builds homodimers, while TLR2 pairs either with TLR1 or TLR6. TLR4 activation ensues when LPS binds to lipopolysaccharide-binding protein (LPB). Cluster of differentiation 14 (CD14) and myeloid differentiation factor-2 (MD-2) are required for TLR4 dimerization. TLR4 signaling can follow two different intracellular pathways. The MyD88-dependent pathway via TIRAP induces the transcription factor nuclear factor-κB (NF-κB) resulting in the release of inflammatory cytokines, e.g., interleukin 6 and tumor necrosis factor-α. Enhanced amounts of reactive oxygen species (ROS) will be produced. Alternatively, the MyD88-independent pathway via TRAM and TRAF leads to the release of type 1 interferons

Fig. 2

Different sources of radical-induced damage-associated molecular patterns (DAMPs). Very different chemical substances and ionizing radiation share that they can generate free radicals in tissue. These distinct substances directly or indirectly cause activation of TLR4 signaling. One common mechanism is that they all induce DAMPs, which activate TLR4 and subsequently cause inflammatory and oxidative and nitrosative stress responses. Activation of the TLR with one agonist causes an enhanced response to a second TLR agonist. Psychological stressors may further augment the responsivity of TLR signaling

Fig. 3

The TLR Radical Cycle. The initial event could be any TLR activation, e.g., an infection, chemotherapy or radiation therapy, exposure to radical inducing environmental substances or in some cases adjuvant agents, either continuous low exposure or a short time high exposure. Key is the release of reactive oxygen species (ROS), which can degrade hyaluronic acid, oxidize phospholipids and can activate high-mobility group protein B1. All these products are damage-associated molecular patterns (DAMPs) that activate the TLR4 pathway resulting in increased production of ROS, reactive nitrogen species, and inflammatory mediators. As a consequence, a vicious cycle may result between TLR activation and ROS production which is independent of the initial event. Blocking this TLR radical cycle offers opportunities to treat many TLR-related diseases. TLR4 antagonist, interference with the signal pathway, and ROS eliminating pharmaceuticals provide possibilities to treat TLR4-induced chronic inflammatory responses