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. 2016 Nov;100(5):1135-1146.
doi: 10.1189/jlb.3A0515-213RR. Epub 2016 Jun 3.

Milk fat globule epidermal growth factor-8 limits tissue damage through inflammasome modulation during renal injury

Marie-Joëlle Brissette  1   2 , Patrick Laplante  1   2 , Shijie Qi  1 , Mathieu Latour  3 , Jean-François Cailhier  4   2   5
Affiliations

Milk fat globule epidermal growth factor-8 limits tissue damage through inflammasome modulation during renal injury

Marie-Joëlle Brissette et al. J Leukoc Biol. 2016 Nov.

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.

Keywords: MFG-E8; NLRP3; fibrosis; macrophage; unilateral ureteral obstruction.

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