Intercalated cells contribute to the immune responses in renal autoimmune disease.

Autoimmune diseases are a major cause of acute and chronic kidney injury, driven by complex mechanisms involving autoantibodies and cellular immune responses that result in tissue damage. Intercalated cells (ICs), specialized renal epithelial cells responsible for proton secretion, are strategically positioned at the epithelial-immune interface, making them ideal sensors of stress signals and potential regulators of immune responses. To investigate the molecular mechanisms by which ICs crosstalk with immune cells during autoimmune kidney injury, we depleted Foxp3+ regulatory T-cells (Tregs) by injecting diphtheria toxin (DT) into male and female Foxp3-DTR mice. This triggered robust renal autoimmune inflammation, characterized by infiltration of neutrophils, macrophages, and T- and B-cells, along with the formation of ectopic lymphoid-like structures. We found elevated renal autoantibodies in urine and serum, with antibody deposition in glomeruli and tubules. We identified several renal antigens targeted by autoantibodies, suggesting a potential role for these antigens in kidney injury. Damage included glomerular hypertrophy, proximal tubular injury, an increased urine albumin/creatinine ratio, and decreased urine output. Disruption of immune tolerance led to upregulation of inflammasome-related genes and IL-33 in ICs, which act as key alarmin signals that promote Treg activation and expansion. Despite their initial depletion, Tregs rebounded at 2 and 8 weeks, particularly the subsets expressing the IL-33 receptor and activation markers. Our findings reveal a novel IC-Treg crosstalk, a potential immune-regulatory mechanism mediated by the IL-33 pathway that promotes renal immune tolerance. Understanding the mechanisms behind autoimmune renal tubular injury is essential for developing targeted therapies and identifying suitable biomarkers.