Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury

Abstract

Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.

P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3

“…Inflammation is an important factor in pathogenesis of the cisplatin-induced renal injury (Faubel et al, 2007;Nozaki et al, 2012). Another plausible mechanism of CDDP toxicity may be the generation of reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), which may interact with DNA, lipids, and proteins (Sun, 1990).…”

IL-36 Receptor Antagonist with Special Emphasis on IL-38

“…Blocking the IL-36Ra or the IL-IR pathway mimicked the effects of IL-38 on the production of Th17 cytokines (98)(99)(100)(101)(102). It has been observed that IL-38 shares primary amino acid homology with ILIRa and IL-36Ra but is inconsistent with binding to the IL-18R (103)(104)(105)(106). Some effects ofIL-38 and IL-36RA remain unclear, for instance, why they decrease pro-inflammatory cytokines in peripheral blood mononuclear cells whereas increased proinflammatory cytokines in dendritic cells.…”

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

“…36 IL-18 is clearly expressed by tubular epithelial cells in addition to infiltrating immune cells, 37 but if the tubular expression of IL-18 is inflammasomedependent or not and its contribution to kidney injury remains under debate. 38,39 The strong induction of IL-18 inside the kidney upon injury has raised much attention as IL-18 could be a useful urinary biomarker of kidney injury as discussed in detail elsewhere. 40 Inflammasome activation by intracellular bacteria or LPS can induce necrotic cell death, referred to as pyroptosis.…”