Tetrachlorobenzoquinone exhibits immunotoxicity by inducing neutrophil extracellular traps through a mechanism involving ROS-JNK-NOX2 positive feedback loop.

Abstract Tetrachlorobenzoquinone (TCBQ) is a common metabolite of persistent organic pollutants pentachlorophenol (PCP) and hexachlorobenzene (HCB). Current reports on the toxicity of TCBQ focused on its reproductive toxicity, neurotoxicity, carcinogenicity and cardiovascular toxicity. However, the possible immunotoxicity of TCBQ remains unclear. The release of neutrophil extracellular traps (NETs) is a recently discovered immune response mechanism, however, excess NETs play a pathogenic role in various immune diseases. In an attempt to address concerns regarding the immunotoxicity of TCBQ, we adopted primary mouse neutrophils as the research object, explored the influence of TCBQ on the formation of NETs. The results showed that TCBQ could induce NETs rapidly in a reactive oxygen species (ROS)-dependent manner. Moreover, TCBQ promoted the phosphorylation of c-Jun N-terminal kinase (JNK) mitogen activated protein kinase (MAPK), but not p38 or extracellular signal related kinase (ERK) in neutrophils. Mechanistically, JNK activation enhanced the expression of NADPH oxidase enzyme 2 (NOX2), which further accelerated the generation of ROS and thus amplified the formation of NETs. The pharmacologic blockage of JNK or NOX2 effectively ameliorated TCBQ-induced ROS and NETs, implying that ROS-JNK-NOX2 positive feedback loop was involved in TCBQ-induced NETs. In conclusion, we speculated that targeting NETs formation would be a promising therapeutic strategy in modulating the immunotoxicity of TCBQ.