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

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 of the pro-inflammatory transcription factor NF-κB in stable reporter cell lines as well as increased mRNA expression and secretion of the proinflammatory 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

The relationship between toddlers’ preference for and learning from child- and adult-directed speech

How do internal and external factors such as preference and caregiver input affect word learning in 18- to 24-month-old children? We tested 48 18- to 24-month-old children in a gaze-contingent IDS/ADS preference task and a word-object association learning task. Additionally, we recorded mothers producing IDS and ADS. First, maternal input differed in its prosodic features between IDS and ADS. Second, children showed no systematic differences when choosing between the IDS and the ADS speaker. Third, children learned novel word-object associations from both IDS and ADS. Fourth, a generalised linear mixed model revealed that a child’s individual preference modulated word learning: Children showed higher target recognition in the register they preferred. We did not find any relationship between maternal input, children’s preference, or their word learning. Together, these results suggest that children between 18 and 24 months were influenced more by their own preferences than by external input in the current setting. Thus, the current study sheds light on how the input a child perceives and the preferences a child forms can influence a child's word learning behaviour early in life

I learn what I like: Children’s preferences but not maternal IDS influence word learning from IDS and ADS

The input a child receives as well as the child’s own preferences can influence their learning. While parents typically use exaggerated infant-directed speech with their child (IDS), children’s preference for IDS varies across development, and even older children learn better from IDS relative to ADS (Ma et al., 2011). Here, we examine whether maternal input and children’s preference for IDS relative to ADS influence their word learning from the two registers. We tested 48 18- to 24-month-olds in a gaze-contingent preference task measuring whether they prefer a woman talking IDS or a woman talking ADS. Subsequently, children were presented with novel objects and their novel labels, with half of the labels in IDS and the other in ADS. At test, two objects were presented side-by-side and one object was labelled while children’s target looking was recorded. Additionally, we recorded mothers’ IDS and ADS. While mothers’ IDS differed from ADS, children did not show a systematic preference for one of the registers. Children learned word-object associations from IDS and ADS, and they showed higher target recognition in the register they preferred. These results reveal how the preferences a child forms can influence a child's word learning behaviour early in life