Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein.
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.
Lech
Maciej
M
Medizinische Poliklinik University of Munich, Munich, Germany.
Avila-Ferrufino
Alejandro
A
Allam
Ramanjaneyulu
R
Segerer
Stephan
S
Khandoga
Alexander
A
Krombach
Fritz
F
Garlanda
Cecilia
C
Mantovani
Alberto
A
Anders
Hans-Joachim
HJ
D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D002452:Cell Count; D002634:Chemotaxis, Leukocyte; D003713:Dendritic Cells / Q000502:physiology*; D004847:Epithelial Cells; D007684:Kidney Tubules / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D022423:Myeloid Cells; D009504:Neutrophils / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications* / Q000276:immunology
D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse