Interleukin-15 in kidney disease and therapeutics

Abstract

Purpose of review: Interleukin 15 (IL-15) is a member of the IL-2 family of common gamma chain receptor cytokines with well described anti-inflammatory, pro-survival and pro-proliferative signaling properties. The cytoprotective role of IL-15 in the kidney is now coming into focus with recent reports of its beneficial actions in various forms of kidney disease. This review will summarize what is currently known about IL-15 signaling in the kidney and highlight recent evidence of its beneficial effects on kidney physiology.

Recent findings: IL-15 and its heterotrimeric receptor are expressed throughout the kidney. Like all IL-2 family cytokines, IL-15 can activate signaling through the Janus Kinase (JAK)/Signal transducer of activated T-cells (STAT), phosphoinositol-3 kinase (PI-3K)/AKT and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways and recent evidence suggests that STAT5B is an essential transcriptional mediator of prosurvival signaling in glomerular visceral epithelial cells (i.e. podocytes). IL-15 has also been shown to suppress pro-apoptotic signaling in models of acute kidney injury and pro-fibrotic signaling in models of chronic kidney disease.

Summary: The cytoprotective properties of IL-15 suggest that it may have potential as a nonimmunosuppresive therapeutic for kidney disease. A novel class of IL-15 immunotherapies has emerged for the treatment cancer and some have demonstrated efficacy in clinical trials. These well tolerated IL-15 agonists could possibly be repurposed for the treatment of kidney disease and warrant further exploration.

Figure 1.. IL-15Rα is expressed podocytes.

Super resolution microscopy of a healthy human glomerulus stained for nuclei (4’,6-diamidino-2-phenylindole; white) the glomerular basement membrane protein agrin (green), the podocyte marker protein synaptopodin (blue) and IL-15Rα (red). IL-15Rα localizes with synaptopodin in podocyte foot processes. Punctate IL-15Rα staining can be observed throughout length of foot processes (white asterisks) and at their bases beside the slit membrane (white arrows).

Figure 2.. IL-15 immunotherapies.

Schematic of representative IL-15 immunotherapies. Recombinant human IL-15 (rhIL-15) was the first to be evaluated in clinical trials in 2015. Other IL-15 superagonist therapies that have been developed include receptor-linked-IL-15 (SO-C101), het-IL-15 and ALT-803. Each of these therapies show potent activation of IL-15 signaling in cells and may be of therapeutic value in the treatment of kidney injury.