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.

Quantification of environmentally persistent free radicals and reactive oxygen species in atmospheric aerosol particles

“…Recently, Lakey et al (2016) have shown that fine particulate matter containing redox-active transition metals, quinones and secondary organic aerosols can increase ROS concentrations in the lung lining fluid to levels characteristic for respiratory diseases. ROS play a central role in chemical transformation of biomolecules, such as proteins and lipids, in lung fluid to form damage associated molecular patterns (DAMPs), which can trigger immune reactions causing inflammation through the tolling receptor radical cycle (Lucas and Maes, 2013). Due to the important implications of adverse aerosol health effects, further studies are warranted to characterize and quantify EPFR and ROS contained in atmospheric aerosol particles in various locations, including highly polluted regions such as East Asia and India.…”

Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes

“…Previously, it has been reported that doses in the range of 0.075-2 Gy increased the expression of TLR4-MD2 in mouse macrophages (12). Additionally, TLR4 was shown to be involved in the induction of radiation resistance (19), cell proliferation and the promotion of radiation-induced lymphomas (20), as well as the promotion of reactive oxygen and nitrogen species (ROS/RNS) causing the aggravation of chronic inflammatory diseases (21). One of the novel activators of TLR4 is HMGB1 (22).…”

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…The consistency of this expressionphenotype pattern may have reflected a specific set of underlying molecular signaling responses that promote a granulocytic inflammatory response activated during suboptimal asthma control. Further inspection of the 316 replicated gene sets revealed two interrelated signaling pathways known to drive granulocytic inflammation: TREM-1, the triggering receptor expressed on myeloid cells 1 (26,27); and LPS. Expressed on monocytes, macrophages, and neutrophils, TREM-1 is an orphan immunoreceptor that amplifies inflammation induced by patternrecognition receptors (28) and interacts with the toll-like receptor 4 to promote LPS-mediated granulocytic inflammation (27,29).…”