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Trichloroethylene (TCE), a commonly used organic solvent, is known to cause trichloroethylene hypersensitivity syndrome (THS), also called occupational medicamentosa–like dermatitis due to TCE (OMDT) in China. OMDT patients presented with severe inflammatory kidney damage, and we have previously shown that the renal damage is related to the terminal complement complex C5b-9. Here, we sought to determine whether C5b-9 participated in TCE-induced immune kidney injury by promoting pyroptosis, a new form of programed cell death linked to inflammatory response, with underlying molecular mechanisms involving the NLRP3 inflammasome. A BALB/c mouse-based model of OMDT was established by dermal TCE sensitization in the presence or absence of C5b-9 inhibitor (sCD59-Cys, 25μg/mouse) and NLRP3 antagonist (MCC950, 10 mg/kg). Kidney histopathology, renal function, expression of inflammatory mediators and the pyroptosis executive protein gasdermin D (GSDMD), and the activation of pyroptosis canonical NLRP3/caspase-1 pathway were examined in the mouse model. Renal tubular damage was observed in TCE-sensitized mice. GSDMD was mainly expressed on renal tubular epithelial cells (RTECs). The caspase-1–dependent canonical pathway of pyroptosis was activated in TCE-induced renal damage. Pharmacological inhibition of C5b-9 could restrain the caspase-1–dependent canonical pathway and rescued the renal tubular damage. Taken together, our results demonstrated that complement C5b-9 plays a central role in TCE-induced immune kidney damage, and the underlying mechanisms involve NLRP3-mediated pyroptosis.

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Viral infection or reactivation seems to be critical in trichloroethylene hypersensitivity syndrome (THS), which is also called occupational medicamentosa-like dermatitis (OMDT) in China. Our previous studies reported that polyinosinic-polycytidylic acid (poly I:C) amplified hepatitis in TCE-sensitized mice. However, whether poly I:C plays a role in TCE-induced renal damage remains to be clarified. To this end, a TCE-sensitized mouse model was established. Renal damage, especially renal endothelial cell dysfunction, was assessed. The activation of high mobility group box protein 1 (HMGB1) was further detected to elucidate the possible role of poly I:C in TCE sensitization-induced renal damage. Our results showed that poly I:C pretreatment aggravated the renal histological changes and dysfunction in TCE-sensitized mice. Renal endothelial cell injuries might be a key driver of kidney damage, in which poly I:C pretreatment acted as an amplifier in TCE sensitization. In addition, poly I:C, combined with Toll-like receptor (TLR) 3, promotes the acetylation and release of HMGB1 from renal endothelial cells. Taken together, our findings highlighted a novel role of poly I:C pretreatment in TCE sensitization-induced renal endothelial cell injuries.