Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein

Maciej Lech, Alejandro Avila-Ferrufino, Ramanjaneyulu Allam, Stephan Segerer, Alexander Khandoga, Fritz Krombach, Cecilia Garlanda, Alberto Mantovani, Hans Joachim Anders

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4109-4118
Number of pages10
JournalJournal of Immunology
Volume183
Issue number6
DOIs
Publication statusPublished - Sep 15 2009

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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