Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury

Abstract

Acute kidney injury (AKI) is a leading cause of morbidity and mortality. Drug-induced/toxic AKI can be caused by a number of therapeutic agents. Cisplatin is an effective chemotherapeutic agent whose administration is limited by significant nephrotoxicity. Therapies to prevent cisplatin-induced AKI are lacking. Although tumor necrosis factor-α (TNF) plays a key role in the pathogenesis of cisplatin nephrotoxicity, the innate immune signaling pathways that trigger TNF generation in this context require elucidation. In this regard, sterile injury triggers the release and activation of both isoforms of interleukin(IL)-1, IL-1α and IL-1β. In turn, stimulation of the interleukin-1 receptor (IL-1R1) by these ligands engages a proinflammatory signaling cascade that induces TNF induction. We therefore hypothesized that IL-1R1 activation exacerbates cisplatin-induced AKI by inducing TNF production, thereby augmenting inflammatory signals between kidney parenchymal cells and infiltrating myeloid cells. IL-1R1+/+ (WT) and IL-1R1−/− (KO) mice were subjected to cisplatin-induced AKI. Compared with WT mice, IL-1R1 KO mice had attenuated AKI as measured by serum creatinine and BUN, renal NGAL mRNA levels, and blinded histological analysis of kidney pathology. In the cisplatin-injured kidney, IL-1R1 KO mice had diminished levels of whole kidney TNF, and fewer Ly6G-expressing neutrophils. In addition, an unbiased machine learning analysis of intrarenal immune cells revealed a diminished number of CD11bint/CD11cintmyeloid cells in IL-1R1 KO injured kidneys compared with IL-1R1 WT kidneys. Following cisplatin, IL-1R1 KO kidneys, compared with WTs, had fewer TNF-producing: macrophages, CD11bint/CD11cintcells, and neutrophils, consistent with an effect of IL-1R1 to polarize intrarenal myeloid cells toward a proinflammatory phenotype. Interruption of IL-1-dependent signaling pathways warrants further evaluation to decrease nephrotoxicity during cisplatin therapy.