Cancer (INCA MDSCAN PRT-K15-136 grant), and the Regional Ligue Contre le Cancer 44. We thank the staff of the Humanized Rodent Platform and MicroPICell Cellular and Tissue Imaging

Key Points• Loss of DGKe in endothelial cells induces cell death, impairs angiogenic responses, and leads to an activated and prothrombotic phenotype.• DGKE silencing in resting endothelial cells does not affect complement activation at their surface.Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregulation of the complement alternative pathway, leading to glomerular endothelial cell (EC) damage and thrombosis. However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an integral component of the complement cascade, led us to consider other pathophysiologic mechanisms for this disease. Here, we demonstrate that loss of DGK« expression/activity in EC induces an increase in ICAM-1 and tissue factor expression through the upregulation of p38-MAPK-mediated signals, thus highlighting a proinflammatory and prothrombotic phenotype of DGK«-deficient ECs. More interestingly, DGKE silencing also increases EC apoptosis and impairs EC migration and angiogenesis in vitro, suggesting that DGKE loss-of-function mutations impair EC repair and angiogenesis in vivo. Conversely, DGKE knockdown moderately decreases the expression of the complement inhibitory protein MCP on quiescent EC, but does not induce complement deposition on their surface in vitro. Collectively, our data strongly suggest that in DGKE-associated aHUS patients, thrombotic microangiopathy results from impaired EC proliferation and angiogenesis rather than complement-mediated EC lesions. Our study expands the current knowledge of aHUS mechanisms and has implications for the treatment of patients with isolated DGKE mutations. (Blood. 2015;125(6):1038-1046 IntroductionAtypical hemolytic uremic syndrome (aHUS) is a severe form of thrombotic microangiopathy (TMA) that affects primarily the kidney. It is characterized by the occurrence of endothelial damage and fibrin/ platelet thrombi in the kidney microvasculature, leading to its typical triad of hemolytic microangiopathic anemia, thrombocytopenia, and acute renal injury.1 aHUS has a poor prognosis, with a 2% to 10% mortality rate, and about two-thirds of patients progress toward end-stage renal disease, and there is a high risk of recurrence of the disease after kidney transplantation.2 Over the past decade, many studies have highlighted the central role of complement alternative pathway dysregulations in the development of aHUS. [3][4][5] Several mutations in genes encoding complement regulatory proteins (factor H, 6 MCP, 7 factor I, 8 thrombomodulin 9 ) or components of the alternative C3 convertase (C3, 10 factor B 11 ), as well as the presence of circulating inhibitory anti-factor H antibodies, 12 have been shown to predispose to the development of aHUS. It is currently assumed that complement alternative pathway activation triggered mainly by infection or pregnancy 13 leads to endothelial cell (EC) damage and TMA. These observations led to the development of complement-targeted therapies for the treatment of aHUS, 14 and eculizumab, a mo...

Resolution of inflammation is elicited by proresolving lipids, which activate GPCRs to induce neutrophil apoptosis, reduce neutrophil tissue recruitment, and promote macrophage efferocytosis. Transcriptional analyses in up to 300 patients with Inflammatory Bowel Disease (IBD) identified potential therapeutic targets mediating chronic inflammation. We found that ChemR23, a GPCR targeted by resolvin E1, is overexpressed in inflamed colon tissues of severe IBD patients unresponsive to anti-TNFα or anti-α4β7 therapies and associated with significant mucosal neutrophil accumulation. We also identified an anti-ChemR23 agonist antibody that induces receptor signaling, promotes macrophage efferocytosis, and reduces neutrophil apoptosis at the site of inflammation. This ChemR23 mAb accelerated acute inflammation resolution and triggered resolution in ongoing chronic colitis models, with a significant decrease in tissue lesions, fibrosis and inflammation-driven tumors. Our findings suggest that failure of current IBD therapies may be associated with neutrophil infiltration and that ChemR23 is a promising therapeutic target for chronic inflammation.