Milk fat globule epidermal growth factor-8 limits tissue damage through inflammasome modulation during renal injury.
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.
Research Centre, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada.|Montreal Cancer Institute, Montreal, Quebec, Canada.
Marie-Joëlle
MJ
Brissette
Research Centre, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada.|Montreal Cancer Institute, Montreal, Quebec, Canada.
Patrick
P
Laplante
Research Centre, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada.
Shijie
S
Qi
Department of Pathology, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada; and.
Mathieu
M
Latour
Research Centre, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada; jf.cailhier@umontreal.ca.|Montreal Cancer Institute, Montreal, Quebec, Canada.|Nephrology Division, Centre Hospitalier de l'Université de Montréal and Université de Montréal, Montreal, Quebec, Canada.
Jean-François
JF
Cailhier
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D017209:Apoptosis; D060833:Cellular Microenvironment; D003094:Collagen / Q000032:analysis; D016219:Immunotherapy, Adoptive; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology*; D007668:Kidney / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D009393:Nephritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D014517:Ureteral Obstruction / Q000150:complications
D000954:Antigens, Surface; D058847:Inflammasomes; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D011994:Recombinant Proteins; D003094:Collagen
MFG-E8; NLRP3; fibrosis; macrophage; unilateral ureteral obstruction