Milk fat globule epidermal growth factor‐8 limits tissue damage through inflammasome modulation during renal injury. Issue 5 (3rd June 2016) - Brissette, Marie‐Joëlle
Abstract : MFG‐E8‐reprogramming of macrophages has a protective role in UUO through inflammasome modulation, preventing severe tissue damage and fibrosis. Abstract : Mediators released by apoptotic renal resident cells play a crucial role in modification of the inflammatory microenvironment. We have demonstrated that milk fat globule epidermal growth factor 8 (MFG‐E8) is released by apoptotic cells, which results in reduced proinflammatory cytokine production by macrophages. The present study was designed to study the role of MFG‐E8 on the modulation of tissue damage and macrophage phenotype in a renal inflammatory model, unilateral ureteral obstruction (UUO). C57BL/6 WT or MFG‐E8 KO mice underwent ureteral ligation for 3, 7, and 14 d to evaluate renal injury. MFG‐E8 (30 µg/kg) or vehicle was also administered i.p. MFG‐E8 administration reduced kidney damage and fibrosis compared with control, whereas its absence in MFG‐E8 KO mice was associated with more severe disease. Moreover, MFG‐E8 administration was associated with decreased inflammasome activation in the kidney. Furthermore, adoptive transfer of MFG‐E8–stimulated macrophages reduced activation of inflammasome and tissue damage. In all cases, both the systemic administration of MFG‐E8 and MFG‐E8–treated macrophages promoted accumulation of anti‐inflammatory CD206 + macrophages. We propose that the protective role of MFG‐E8 is mediated through anti‐inflammatory macrophage reprogramming which results in decreased inflammasome activation, preventing severe tissue damage. These data provide valuable insight for identification of MFG‐E8 as a novel target in modulation of inflammatory diseases.