The pathological role of IL-18Rα in renal ischemia/reperfusion injury

Interleukin (IL)-18 is a proinflammatory cytokine produced by leukocytes and parenchymal cells (eg, tubular epithelial cells (TECs), mesangial cells, and podocytes). IL-18 receptor (IL-18R) is expressed on these cells in the kidney during ischemia/reperfusion injury (IRI), but its role in this injury is unknown. Fas/Fas ligand (FasL) is also involved in the pathogenesis of renal IRI via tubular apoptosis. In addition, IL-18 enhances the expression of FasL on TECs, but the mechanism underlying this enhancement is not known. Here we used IL-18R alpha-deficient mice to explore the pathological role of IL-18R alpha in renal IRI. We found that compared to wild-type (WT) mice with renal IRI as an acute kidney injury (AKI), the IL-18R alpha-deficient mice demonstrated decreased renal function (as represented by blood urea nitrogen), tubular damage, an increased accumulation of leukocytes (CD4+ T cells, neutrophils, and macrophages), upregulated early AKI biomarkers (ie, urinary kidney injury molecule-1 levels), and increased mRNA expressions of proinflammatory cytokines (IL-1 beta, IL-12p40, and IL-18) and chemokines (intercellular adhesion molecule-1 and CCL2/monocyte chemoattractant protein-1). The mRNA expression of FasL in the kidney was increased in the IL-18R alpha-deficient mice compared to the WT mice. The adoptive transfer of splenocytes by WT mice led to decreased renal IRI compared to the IL-18R alpha-deficient mice. In vitro, the mRNA expression of FasL on TECs was promoted in the presence of recombinant IL-18. These data reveal that IL-18R alpha has an anti-inflammatory effect in IRI-induced AKI. Above all, IL-18 enhanced the inflammatory mechanisms and the apoptosis of TECs through the Fas/FasL pathway by blocking IL-18R alpha.