Chemical modification of pro-inflammatory proteins by peroxynitrite increases activation of TLR4 and NF-κB: Implications for the health effects of air pollution and oxidative stress

Abstract

Environmental pollutants like fine particulate matter can cause adverse health effects through oxidative stress and inflammation. Reactive oxygen and nitrogen species (ROS/RNS) such as peroxynitrite can chemically modify proteins, but the effects of such modifications on the immune system and human health are not well understood. In the course of inflammatory processes, the Toll-like receptor 4 (TLR4) can sense damage-associated molecular patterns (DAMPs). Here, we investigate how the TLR4 response and pro-inflammatory potential of the proteinous DAMPs α-Synuclein (α-Syn), heat shock protein 60 (HSP60), and high-mobility-group box 1 protein (HMGB1), which are relevant in neurodegenerative and cardiovascular diseases, changes upon chemical modification with peroxynitrite. For the peroxynitrite-modified proteins, we found a strongly enhanced activation of TLR4 and the pro-inflammatory transcription factor NF-κB in stable reporter cell lines as well as increased mRNA expression and secretion of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-8 in human monocytes (THP-1). This enhanced activation of innate immunity via TLR4 is mediated by covalent chemical modifications of the studied DAMPs. Our results show that proteinous DAMPs modified by peroxynitrite more potently amplify inflammation via TLR4 activation than the native DAMPs, and provide first evidence that such modifications can directly enhance innate immune responses via a defined receptor. These findings suggest that environmental pollutants and related ROS/RNS may play a role in promoting acute and chronic inflammatory disorders by structurally modifying the body's own DAMPs. This may have important consequences for chronic neurodegenerative, cardiovascular or gastrointestinal diseases that are prevalent in modern societies, and calls for action, to improve air quality and climate in the Anthropocene.

Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts

“…Oxidative stress is the result from imbalance between reactive oxygen species (ROS) overproduction and endogenous antioxidants. Excessive ROS triggered multifarious cellular stress response, such as endoplasmic reticulum (ER) stress, inflammatory reaction, genotoxic stress and hypoxia [ [70] , [71] , [72] , [73] ]. A recent plant study found ROS induced the activation of GCN2 kinase in Arabidopsis [ 74 ].…”

Special Issue "Impact of environmental pollution and stress on redox signaling and oxidative stress pathways"

“…They also provide evidence for the protective potential of antioxidant cosmeceuticals. Ziegler & Pöschl report about the increased pro-inflammatory potential of nitrated α-synuclein, heat shock protein 60 and high-mobility-group box 1 protein, which are relevant in neurodegenerative and cardiovascular diseases, by measuring the activation of the Toll-like receptor 4 in cultured human monocytes (THP-1) [ 19 ]. The authors employed nitrated proteins as a model of damage-associated molecular patterns that arise upon reaction of endogenous proteins with nitrogen oxide radicals from air pollution or peroxynitrite generated by immune cells in response to stimulation by solid particulate matter.…”

“…We also put emphasis on emerging mechanisms based on dysregulation of the circadian clock, the microbiome, epigenetic pathways and cognitive function by environmental stressors. Several articles within this Special Issue thematically cover chemical environmental stressors such as air pollution [ [18] , [19] , [20] ], nano/microplastic particles [ 21 ], other toxic environmental chemicals (e.g. heavy metals or pesticides as well as airborne secondary toxicants) [ [22] , [23] , [24] ] and the behavioral risk factor waterpipe smoking [ 25 ].…”

Ceylon cinnamon and its major compound Cinnamaldehyde can limit overshooting inflammatory signaling and angiogenesis in vitro: implications for COVID-19 treatment

“…Moreover, damage-associated molecular patterns (DAMPs) like heat shock protein 60 (HSP60), high mobility group box 1 (HMGB1), and calprotectin (S100A8/A9 hetero tetramer) can be released during immune reactions elicited by COVID-19 infection (13)(14)(15)(16). These DAMPs can activate pattern recognition receptors such as TLR2, TLR4, and RAGE (14,(16)(17)(18)(19) and generate additional positive feedback via NF-κB, as has been shown for TLR4 (Fig. 1), causing further cytokine release.…”