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 language | English |
|---|---|
| Pages (from-to) | 4109-4118 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 183 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Sep 15 2009 |
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ASJC Scopus subject areas
- Immunology
- Medicine(all)
Cite this
Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein. / Lech, Maciej; Avila-Ferrufino, Alejandro; Allam, Ramanjaneyulu; Segerer, Stephan; Khandoga, Alexander; Krombach, Fritz; Garlanda, Cecilia; Mantovani, Alberto; Anders, Hans Joachim.
In: Journal of Immunology, Vol. 183, No. 6, 15.09.2009, p. 4109-4118.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein
AU - Lech, Maciej
AU - Avila-Ferrufino, Alejandro
AU - Allam, Ramanjaneyulu
AU - Segerer, Stephan
AU - Khandoga, Alexander
AU - Krombach, Fritz
AU - Garlanda, Cecilia
AU - Mantovani, Alberto
AU - Anders, Hans Joachim
PY - 2009/9/15
Y1 - 2009/9/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.0900118
DO - 10.4049/jimmunol.0900118
M3 - Article
VL - 183
SP - 4109
EP - 4118
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 6
ER -