Ischemia reperfusion induces IFN regulatory factor 4 in renal dendritic cells, which suppresses postischemic inflammation and prevents acute renal failure.
Ischemia reperfusion (IR) activates TLRs causing subsequent sterile inflammation, for example in postischemic acute renal failure. Unexpectedly, TLR signaling predominates in intrinsic renal cells and not in intrarenal APCs in the postischemic kidney. We hypothesized that certain factors suppress APC activation and thereby limit sterile renal inflammation, for example, IFN regulatory factor 4 (IRF-4), an inducible inhibitor of LPS signaling. Oxidative stress was a trigger for IRF4 induction in myeloid cells in vitro as well as in CD45(+)/CD11c+ cells in the postischemic kidney. Lack of IRF4 aggravated acute renal failure 24 h after renal artery clamping together with increased intrarenal expression of TNF-alpha, IL-6, CXCL2, and CCL2 as well as excessive tubular necrosis and peritubular neutrophil influx as compared with wild-type IR kidneys. This effect almost entirely depended on the role of IRF4 to suppress TNF-alpha release by intrarenal APCs because either clodronate liposome depletion of these cells or TNF-alpha blockade with etanercept entirely abrogated the aggravation of cytokine expression and acute renal failure in Irf4-deficient mice. Thus, loss-of-function mutations in the IRF4 gene predispose to IR injury because the postischemic induction of IRF4 in resident APCs like CD11c(+) dendritic cells, suppresses them to secrete TNF-alpha, and thereby limits inappropriate immunopathology.
Lassen
Saraswati
S
Medizinische Poliklinik, Universität München, München, Germany.
Lech
Maciej
M
Römmele
Christoph
C
Mittruecker
Hans-Willi
HW
Mak
Tak W
TW
Anders
Hans-Joachim
HJ
D058186:Acute Kidney Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D039521:CD11c Antigen / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000099218:Interferon Regulatory Factor-4
D039521:CD11c Antigen; D050835:Interferon Regulatory Factors; D017493:Leukocyte Common Antigens; D000099218:Interferon Regulatory Factor-4