Ischemia-reperfusion induces interferon-regulatory-factor-4 in renal dendritic cells which suppresses postischemic inflammation and prevents acute renal failure. (98.1)

Abstract

Abstract Acute renal failure is still a serious medical problem that causes substantial morbidity and mortality. Ischemia-reperfusion (IR) activates TLRs causing inflammation and kidney injury. We hypothesized that certain factors suppress dendritic cell activation and thereby limit sterile renal inflammation, e.g. interferon-regulatory-factor (IRF)-4. Bi- or unilateral renal clamping was carried out for C57BL/6 (WT) and IRF4-knockout (IRF4-/-) mice. Known functions of the transcription factor IRF4 are the maturation of B cells, T cells and macrophages. Oxidative stress induced IRF4 expression in myeloid cells in-vitro as well as in the postischemic kidney. Lack of IRF4 aggravated acute renal failure after renal artery clamping together with increased intrarenal expression of TNF-α, IL-6, CXCL2, and CCL2 as well as excessive tubular necrosis and neutrophil influx. Consistent with these results we observed higher creatinine and urea levels in the serum of IRF4-/-mice after IR. This effect almost entirely depended on the role of IRF4 to suppress TNF-α release by intrarenal dendritic cells. Both clodronate depletion of these cells and TNF-α 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 dendritic cells suppresses them to secrete TNF-α and thereby limits immunopathology.