Infusion of IL-10–expressing cells protects against renal ischemia through induction of lipocalin-2

Abstract

Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow-derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1 h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10-mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10-mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.

Pterostilbene protects against acute renal ischemia reperfusion injury and inhibits oxidative stress, inducible nitric oxide synthase expression and inflammation in rats via the Toll‑like receptor 4/nuclear factor‑κB signaling pathway

“…Following stimulation of NF-κB signaling pathways via death-1/B7-Hl, IL-10 was upregulated (20). By employing the IL-10 monoclonal antibody for neutralization, the level of pro-inflammatory factors, such as TNF-α and IL-6 are increased (21). In the present study, Pter treatment significantly suppressed the expression levels of IL-1β, IL-6 and TNF-α, and significantly increased IL-10 expression levels in renal IRI rats.…”

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

“…20 Overexpressing IL-10 via adoptive transfer reduced inflammation and kidney injury dependent on increased expression of NGAL, its receptor, and a supply of intracellular iron. Our study extends this finding by demonstrating in a postoperative setting that the protective effects of high IL-10 may be modified by NGAL.…”

“…[14][15][16][17][18][19] We hypothesized that our cohort would also show these trends. Notably, a preclinical study 20 has demonstrated that IL-10 protects against renal ischemia through the induction of neutrophil gelatinase-associated lipocalin (NGAL), an established AKI biomarker that our group has previously studied. Thus, we evaluated whether elevated NGAL modified any observed protective effects of IL-10 in humans.…”

Neutrophil gelatinase-associated lipocalin as a potential therapeutic integrator of glycolipid metabolic and inflammatory signaling

“…25 Several inflammatory stimuli, such as lipopolysaccharides, IL-1β, IL-9, IL-10 can markedly induce NGAL expression and secretion in macrophages and adipocytes. [30][31][32] NGAL is strongly induced by the pro-inflammatory cytokine interleukin-1β via nuclear factor-κB activation, but not by the profibrotic cytokines platelet-derived growth factor and transforming growth factor-β. 33 The proinflammatory transcription factor NF-κB has been shown to trans activate NGAL expression through binding with a consensus motif in the promoter region of the NGAL gene.…”