SAP130 released by ferroptosis tubular epithelial cells promotes macrophage polarization via Mincle signaling in sepsis acute kidney injury.

The pathological mechanism of sepsis-associated acute kidney injury (SA-AKI) is complex and involves tubular epithelial cell (TEC) death and immune cell activation. However, the interaction between tubular cell death and macrophage-mediated inflammation remains unclear. In this study, we uncovered that TEC ferroptosis was activated in SA-AKI. Increased levels of ferroptotic markers, including ferroptosis-related proteins, lipid peroxidation, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), reactive oxygen species (ROS), and mitochondrial damage, were observed in the kidney tissue of cecum ligation and puncture (CLP) and Lipopolysaccharide (LPS)-induced SA-AKI mouse models, which were subsequently suppressed by Ferrostatin-1 (Fer-1). In vitro experiments showed that Fer-1 inhibits LPS-induced mitochondrial damage, Fe accumulation, and cytosolic ROS production. Moreover, it was found that TEC ferroptosis induced by promoted macrophage-inducible C-type lectin (Mincle) and its downstream expression and M1 polarization, which was mediated by the release of spliceosome-associated protein 130 (SAP130), an endogenous ligand of Mincle, from TEC. It was confirmed in vitro that the supernatant from LPS-stimulated TECs promoted Mincle expression and M1 polarization in macrophages. Further experiments revealed that M1 macrophages aggravated TEC ferroptosis, which was offset by neutralizing SAP130 or inhibiting Mincle expression. In addition, neutralizing the circulatory SAP130 blunted kidney ferroptosis and Mincle expression, as well as macrophage infiltration in the kidney of SA-AKI mice. In conclusion, the release of SAP130 from ferroptotic TECs promoted M1 macrophage polarization by triggering Mincle/syk/NF-κB signaling, and M1 macrophages, in turn, aggravated TEC ferroptosis.