Combined negative effects of microplastics and plasticizer DEHP: The increased release of Nets delays wound healing in mice

Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.

Microplastics are ubiquitous environmental contaminants leading to inevitable human exposure. Even so, little is known about the effects of microplastics in human health. Thus, in this work we review the evidence for potential negative effects of microplastics in the human body, focusing on pathways of exposure and toxicity. Exposure may occur by ingestion, inhalation and dermal contact due to the presence of microplastics in products, foodstuff and air. In all biological systems, microplastic exposure may cause particle toxicity, with oxidative stress, inflammatory lesions and increased uptake or translocation. The inability of the immune system to remove synthetic particles may lead to chronic inflammation and increase risk of neoplasia. Furthermore, microplastics may release their constituents, adsorbed contaminants and pathogenic organisms. Nonetheless, knowledge on microplastic toxicity is still limited and largely influenced by exposure concentration, particle properties, adsorbed contaminants, tissues involved and individual susceptibility, requiring further research.

Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.