Macrophages are not the source of injurious interleukin-18 in ischemic acute kidney injury in mice.
We previously reported in ischemic acute kidney injury (AKI) in mice that caspase-1-mediated production of interleukin-18 (IL-18) is pathogenic and that macrophage depletion by liposome-encapsulated clodronate (LEC) is protective. Therefore, our aim was to determine whether macrophages are a source of IL-18 in ischemic AKI in mice. On immunofluorescence staining of the outer stripe of outer medulla, the number of macrophages double stained for CD11b and IL-18 was significantly increased in AKI and significantly decreased by LEC. Adoptive transfer of RAW 264.7 cells, a mouse macrophage line that constitutively expresses IL-18 mRNA, reversed the functional protection against AKI in both LEC-treated wild-type and caspase-1 -/- mice. To test whether IL-18 in macrophages is necessary to cause AKI, we adoptively transferred macrophages in which IL-18 was inhibited. Peritoneal macrophages isolated from wild-type mice, IL-18 binding protein transgenic (IL-18 BP Tg) mice, and IL-18 -/- mice were used. IL-18 BP Tg mice overexpress human IL-18 BP and exhibit decreased biological activity of IL-18. Adoptive transfer of peritoneal macrophages from wild-type as well as IL-18 BP Tg and IL-18 -/- mice reversed the functional protection against AKI in LEC-treated mice. In summary, adoptive transfer of RAW cells, that constitutively express IL-18, reverses the functional protection in macrophage-depleted wild-type and caspase-1 -/- mice with AKI. However, adoptive transfer of peritoneal macrophages in which IL-18 function was inhibited also reverses the functional protection in macrophage-depleted mice. In conclusion, IL-18 from adoptive transfer of macrophages is not sufficient to cause ischemic AKI.
He
Zhibin
Z
Division of Renal Diseases, University of Colorado Denver and the Health Sciences Center, Aurora, Colorado 80262, USA.
Dursun
Belda
B
Oh
Dong-Jin
DJ
Lu
Lawrence
L
Faubel
Sarah
S
Edelstein
Charles L
CL
D058186:Acute Kidney Injury / Q000276:immunology / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D020382:Interleukin-18 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism
D039481:CD11b Antigen; D020382:Interleukin-18; D012333:RNA, Messenger; D020170:Caspase 1