Crosstalk Between Clec7a and TLR4 Immune Pathway Drives Renal Damage in a Cisplatin-Induced Acute Kidney Injury Model.

Abstract

Macrophage-associated immune responses play a critical role in acute kidney injury (AKI). Clec7a, primarily expressed on activated myeloid cells, functions as a pattern recognition receptor essential for regulating immune homeostasis. However, its specific effects and roles during AKI remain unclear. To investigate the role of Clec7a in AKI, we used a cisplatin-induced acute kidney injury (cis-AKI) model. We administered the Clec7a antagonist laminarin (LAM) and performed macrophage depletion. Additionally, we utilized siRNA to silence Clec7a and transferred Clec7a-expressing primary peritoneal macrophages (PPMs) to mice to explore potential therapeutic targets. Chromatin immunoprecipitation (ChIP) assays were conducted to demonstrate the physical binding of NF-κB/P65 to the Clec7a promoter. Our findings revealed an increase in Clec7a-expressing macrophages in the cis-AKI model. Blocking Clec7a signaling with LAM alleviated cisplatin-induced renal inflammation, an effect also observed with the knockdown of Clec7a in transferred PPMs. Notably, this study shows that Clec7a activation by its agonist d-Zymosan induces renal inflammation and up-regulates iNOS in C57BL/6 mice. Furthermore, both TLR4 and NF-κB inhibitors were able to antagonize LPS-induced Clec7a expression. ChIP assays confirmed the physical binding of NF-κB to the Clec7a promoter, indicating the regulatory effect of the TLR4/NF-κB signaling pathway on Clec7a expression. The synergistic signaling crosstalk between Clec7a-Syk and TLR4/NF-κB promotes and sustains the inflammatory phenotypes of M1 macrophages, contributing to damage in AKI. These findings provide novel insights into the pivotal role of Clec7a in renal inflammation and suggest its potential as a therapeutic target for AKI.