Inflammatory kidney injury in trichloroethylene hypersensitivity syndrome mice: Possible role of C3a receptor in the accumulation of Th17 phenotype

Abstract

Trichloroethylene (TCE) is a common organic solvent which can cause TCE hypersensitivity syndrome (THS) in exposure workers. THS is an adverse skin disorder with severe inflammatory kidney damage. Complement C3a receptor (C3aR) acts as a specific receptor for the key complement cleavage product C3a and involves multiple inflammatory responses, but the role of C3aR in TCE induced kidney inflammatory injury remains unknown. In this study, BALB/c mouse model of skin sensitization induced by TCE was set up in the presence or absence of C3aR antagonist (C3aRA). Kidney pathology and renal function, expression of inflammatory mediators and C3aR, changes in Th17 cell numbers, and activation of signal transducer and activator of transcription 3 (STAT3) in the kidney were examined. TCE sensitization produced histopathological and functional damage to the kidney, accompanied by increased levels of interleukin (IL-) 1β, IL-6, and IL-23. Local accumulation of Th17 cells and enhanced phosphorylation of STAT3 were also seen in the impaired kidney in TCE sensitization-positive mice. C3aR was mainly located in the impaired glomerulus and upregulated in TCE sensitization-positive mice. C3aRA pretreatment alleviated the structural and functional kidney damage and the inflammatory cytokine and Th17 responses by TCE sensitization, and specifically reduced the phosphorylation of STAT3. Together, our results demonstrate that C3aR signaling promotes the inflammatory responses and regulates the accumulation of Th17 phenotype via phosphorylation of STAT3 in TCE sensitization induced inflammatory kidney damage. C3aR may serve as a potential therapeutic target in TCE sensitization mediated kidney injury.