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Published on: November 10, 2021
Milk fat globule epidermal growth factor-8 limits tissue damage through inflammasome modulation during renal injury
Marie-Joëlle Brissette1,2, Patrick Laplante1,2, Shijie Qi1
1Research Centre, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada.
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.
Insights
Milk fat globule epidermal growth factor 8 (MFG-E8) reduces kidney inflammation and damage by reprogramming macrophages to an anti-inflammatory state. Its absence worsens renal injury, highlighting MFG-E8
Area of Science:
- Renal inflammation and immunology
- Cellular mediators of inflammation
- Macrophage biology
Background:
- Apoptotic cells release mediators that influence the inflammatory microenvironment.
- Milk fat globule epidermal growth factor 8 (MFG-E8), released by apoptotic cells, reduces proinflammatory cytokine production by macrophages.
Purpose of the Study:
- To investigate the role of MFG-E8 in modulating tissue damage and macrophage phenotype in a unilateral ureteral obstruction (UUO) model of renal inflammation.
- To assess the therapeutic potential of MFG-E8 in preventing kidney injury.
Main Methods:
- Utilized C57BL/6 wild-type (WT) and MFG-E8 knockout (KO) mice subjected to UUO for 3, 7, and 14 days.
- Administered MFG-E8 intraperitoneally (i.p.) to evaluate its protective effects.
- Investigated the impact of adoptive transfer of MFG-E8-stimulated macrophages.
Main Results:
- MFG-E8 administration significantly reduced kidney damage and fibrosis in the UUO model.
- Absence of MFG-E8 (in KO mice) exacerbated renal injury and disease severity.
- MFG-E8 treatment decreased inflammasome activation and promoted the accumulation of anti-inflammatory CD206+ macrophages.
- Adoptive transfer of MFG-E8-stimulated macrophages also reduced inflammasome activation and tissue damage.
Conclusions:
- MFG-E8 plays a protective role in renal inflammation by reprogramming macrophages towards an anti-inflammatory phenotype.
- This reprogramming leads to decreased inflammasome activation, thereby preventing severe tissue damage.
- MFG-E8 represents a novel therapeutic target for modulating inflammatory kidney diseases.
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