Sphingosine‐1‐phosphate signalling induces the production of Lcn‐2 by macrophages to promote kidney regeneration

Abstract

Inflammatory reactions are initiated to eliminate pathogens, but also to promote repair of damaged tissue after acute inflammation is terminated. In this regard, macrophages play a prominent role during induction as well as resolution of inflammation and injury in various organs including the kidney. The present study describes a mechanism for renal tissue regeneration after ischaemia/reperfusion injury. Following injury, apoptotic cell‐derived sphingosine‐1‐phosphate (S1P) or exogenously administered sphingosine analogue FTY720 activates macrophages to support the proliferation and healing of renal epithelium, once inflammatory conditions are terminated. Both suppression of inflammation and renal regeneration might require S1P receptor 3 (S1P3) signalling and downstream release of neutrophil gelatinase‐associated lipocalin (NGAL/Lcn‐2) from macrophages. Overall, our data point to a macrophage‐dependent S1P‐S1P3‐Lcn‐2 axis that might be beneficial for restoration of kidney function after an ischaemic insult. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

An update on the biology of sphingosine 1-phosphate receptors

“…This could be a cell subtype-specifi c effect, or dependent on environment, as local administration of FTY720 appeared to enhance recruitment of anti-infl ammatory pro-angiogenic monocytes ( 105 ). This supports an earlier report that macrophage S1P 3 induces a pro-regenerative phenotype in a model of renal ischemia/reperfusion ( 106 ). A report utilizing the zymosan peritonitis model proposed that the resulting apoptotic neutrophils induced S1P 1 expression on recruited macrophages and that S1P 1 is necessary for emigration from the infl amed peritoneum, but has no role in efferocytosis or activation ( 107 ).…”

Interleukin-10-Induced Neutrophil Gelatinase-Associated Lipocalin Production in Macrophages with Consequences for Tumor Growth

“…Having proproliferative and regenerative actions of NGAL in mind (15,39), we looked into a protumorigenic capacity of macrophage-derived NGAL. We generated macrophage-conditioned medium (MCM) from primary human macrophages stimulated with IL-10 for 3 h. In turn, MCF-7 breast cancer cells were then treated either with 80 ng/ml of recombinant human NGAL or MCM.…”

“…Conversely, NGAL induces cell death in neutrophils and lymphocytes, probably to limit inflammation, whereas nonhematopoietic cells and macrophages are resistant (7). Furthermore, we previously showed that apoptotic tumor cells activate the production and secretion of NGAL in macrophages, with the subsequent polarization of these macro-phages toward the M2 phenotype (39). Blocking NGAL production in macrophages reduced protective effects achieved with IL-10-overexpressing macrophages in a kidney ischemia/reperfusion injury model, substantiating NGAL-associated proproliferative and anti-inflammatory properties (15).…”

Recovery from Glycerol-Induced Acute Kidney Injury Is Accelerated by Suramin

“…Thus, it seems possible that when proximal tubular cells are exposed to iron-mediated oxidative stress (resulting from glycerol-mediated rhabdomyolysis and release of heme from circulating myoglobin in the tubular lumen) increased NGAL may be produced. It also is documented that NGAL is up-regulated during the time of kidney damage and participates in nephrogenic repair and regeneration (Mishra et al, 2003(Mishra et al, , 2004Mori et al, 2005;Schmidt-Ott et al, 2007;Sola et al, 2011). However, the mechanism(s) by which suramin increased proximal tubular NGAL expression currently remains unknown.…”