Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1

Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA(4)) attenuated TGF-β1–induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-β1 suppressed expression of let-7c. In cells pretreated with LXA(4), upregulation of let-7c persisted despite subsequent stimulation with TGF-β1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA(4) analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-β1 signaling pathway, including the TGF-β receptor type 1. Consistent with this, LXA(4)-induced upregulation of let-7c inhibited both the expression of TGF-β receptor type 1 and the response to TGF-β1. Overexpression of let-7c mimicked the antifibrotic effects of LXA(4) in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA(4). Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA(4)-mediated upregulation of let-7c suppresses TGF-β1–induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis

Neutrophils as protagonists and targets in chronic inflammation

Traditionally, neutrophils have been acknowledged to be the first immune cells that are recruited to an inflamed tissue and have mainly been considered in the context of acute inflammation. By contrast, their importance during chronic inflammation has been studied in less depth. This Review aims to summarize our current understanding of the roles of neutrophils in chronic inflammation, with a focus on how they communicate with other immune and non-immune cells within tissues. We also scrutinize the roles of neutrophils in wound healing and the resolution of inflammation, and finally, we outline emerging therapeutic strategies that target neutrophils.</p