Oxalate Induced Mitochondrial and Lysosomal Dysfunction in Myeloid Cells is Mediated by IL‐10 Signaling

Abstract

Oxalate is a small molecule found in several foods and is excreted in the urine. Accumulation of oxalate in the kidney can lead to crystal and kidney stone formation. Oxalate crystals have been reported to stimulate inflammation and injure renal epithelial cells. However, the effect of CaOx crystals on monocytes and macrophages is not fully‐characterized. Studies from our laboratory have shown that oxalate reduces mitochondrial metabolism and induces oxidative stress in monocytes and macrophages. The purpose of this study was to investigate additional mechanisms of oxalate‐induced changes in myeloid cells. Healthy adults were recruited for these studies and asked to consume a controlled oxalate diet for three days followed by a high oxalate load. Circulating monocytes and plasma were collected from participants before and after the oxalate load. Monocytes were examined using RNA‐sequencing, and plasma cytokine levels were evaluated using ELISA. Human primary macrophages and THP‐1 differentiated macrophages were used to assess mitochondrial quality control and lysosomal function following 24‐hour oxalate exposure using qRT‐PCR, western blotting, and microscopy. Transcriptomics revealed that 1,197 genes were differentially expressed in circulating monocytes following the oxalate load. Genes related to mitochondrial respiration, mitochondrial membrane potential, mitochondrial dysfunction, and IL‐10 signaling (regulator of mitochondrial metabolism) were significantly modified by oxalate. IL‐10 plasma cytokine levels were also significantly reduced. Macrophages exposed to oxalate had an accumulation of dysfunctional mitochondria and reduced lysosomal integrity. The findings from these studies indicate IL‐10 signaling may play a role in regulating mitochondrial quality control and lysosomal function in myeloid cells in response to oxalate. Additional studies investigating the significance of IL‐10 signaling on myeloid cells during crystal and stone formation are warranted.