Lipocalin-2 abrogates epithelial cell cycle arrest by PPARγ inhibition

Macrophage-epithelial cross-talk regulates cell cycle progression and represents an important factor in rescuing epithelial cells from cell cycle arrest in order to maintain a healthy epithelial phenotype. However, the underlying mechanisms are still not well defined. We provide evidence that macrophage-secreted lipocalin-2 (Lcn-2) plays a key role during this process. In a co-culture setup using cell cycle arrested NRK52e renal epithelial cells and primary bone marrow-derived macrophages, Lcn-2 restores proliferation through inhibition of peroxisome proliferator-activated receptor (PPAR)-γ. Lcn-2 overexpression in macrophages overcomes epithelial cell cycle arrest and enhances epithelial markers via megalin and the downstream activation of PI3K/Akt signalling pathway, whereas a knockdown of Lcn-2 in macrophages prevented this effect. Our results show that macrophage-secreting Lcn-2 is crucial in rescuing epithelial cells from cell cycle arrest and in promoting epithelial proliferation.Financial support of this study came from grants from Fondo de Investigación Sanitaria (FIS) PI1701411 (awarded to A.S.) and SAF2015-67770-R from Ministerio de Economia y Competitividad (awarded to G.H.). A.S. was supported by Miguel Servet II contracting system (CPII 14/00026) and M.J. was supported by a grant from Fritz Thyssen Stiftung (Az.10.12.2.156) and a young researcher grant from Goethe-University Frankfurt (Focus Line B).Peer reviewe