Int Immunopharmacol. 2022 Nov 11. pii: S1567-5769(22)00917-1. [Epub ahead of print]113(Pt B):
109432
Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) is a systemic allergic disease similar to drug eruption-like dermatitis that occurs in workers after exposure to trichloroethylene. In addition to skin and mucosa damage, OMDT patients often accompanied by severe multiorgan damage, including kidney injury. However, the mechanism remains unclear. The aim of our research was to explore the role of increased cytosolic mitochondrial DNA in the activation of cGAS-STING signaling and in the kidney injury of trichloroethylene sensitization mice using a mouse model and an in vitro model. By analyzing the kidneys of TCE-sensitized mice, we found obvious tubular mitochondrial damage, decreased expression of COX-IV and TFAM proteins and increased cytosolic mitochondrial DNA in TCE-sensitized-positive mice. Further study found that cytosolic mitochondrial DNA activated cGAS-STING signaling, resulting in the nuclear translocation of P-IRF3 and NF-κB P65 and the transcription and synthesis of type Ⅰ interferons and cytokines, which ultimately led to immune kidney injury in trichloroethylene-sensitized mice. Interestingly, pretreatment with C-176, a STING inhibitor, not only blocked the nuclear translocation of P-IRF3 and NF-κB P65, but also alleviated the kidney injury induced by TCE sensitization. Consistently, in vitro studies also found that mitochondrial DNA pretreatment can activate the cGAS-STING pathway, causing the nuclear translocation of P-IRF3 and NF-κB P65 and the transcription of type Ⅰ interferons and cytokines in HK-2 cells. Overall, our results suggested that cytosolic mitochondrial DNA plays an important role in the activation of the cGAS-STING pathway and TCE sensitization-induced immune kidney injury.
Keywords: Immune kidney injury; Mitochondrial DNA; OMDT; Trichloroethylene sensitization; cGAS-STING