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* Medizinische Poliklinik University of Munich, Munich, Germany;
Clinic for Nephrology, University Hospital, Zurich, and Institute of Anatomy, University of Zurich, Zurich, Switzerland;
Walter Brendel Center for Experimental Medicine, Munich, Germany; and
Istituto Clinico Humanitas, Rozzano, Italy
Ischemia-reperfusion (IR) triggers tissue injury by activating innate immunity, for example, via TLR2 and TLR4. Surprisingly, TLR signaling in intrinsic renal cells predominates in comparison to intrarenal myeloid cells in the postischemic kidney. We hypothesized that immune cell activation is specifically suppressed in the postischemic kidney, for example, by single Ig IL-1-related receptor (SIGIRR). SIGIRR deficiency aggravated postischemic acute renal failure in association with increased renal CXCL2/MIP2, CCL2/MCP-1, and IL-6 mRNA expression 24 h after IR. Consistent with this finding interstitial neutrophil and macrophage counts were increased and tubular cell necrosis was aggravated in Sigirr-deficient vs wild-type IR kidneys. In vivo microscopy revealed increased leukocyte transmigration in the postischemic microvasculature of Sigirr-deficient mice. IL-6 and CXCL2/MIP2 release was much higher in Sigirr-deficient renal myeloid cells but not in Sigirr-deficient tubular epithelial cells after transient hypoxic culture conditions. Renal IR studies with chimeric mice confirmed this finding, as lack of SIGIRR in myeloid cells largely reproduced the phenotype of renal IR injury seen in Sigirr–/– mice. Additionally, clodronate depletion of dendritic cells prevented the aggravated renal failure in Sigirr–/– mice. Thus, loss of function mutations in the SIGIRR gene predispose to acute renal failure because SIGIRR prevents overshooting tissue injury by suppressing the postischemic activation of intrarenal myeloid cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft (AN372/9-1 and GRK 1202) and by the European Union Integrated Projects INNOCHEM (FP6-518167) to H.J.A. and MUGEN to C.G. and A.M. Parts of this project were prepared as a doctoral thesis at the Faculty of Medicine, University of Munich, by A.A.-F.
2 M.L. and A.A-F. contributed equally to the results of this study.
3 Address correspondence and reprint requests to Dr. Hans-Joachim Anders, Medizinische Poliklinik, Universität München, Pettenkoferstrasse 8a, 80336 München, Germany. E-mail address: hjanders{at}med.uni-muenchen.de
4 Abbreviations used in this paper: IR, ischemia-reperfusion; IRI, ischemia-reperfusion injury; PAS, periodic acid-Schiff; SIGIRR, single Ig IL-1-related receptor; TIR, Toll-IL-1 receptor.
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